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1.
Oakes, Patrick William.
The Liquid Crystalline Transition of F-actin and Neutrophil
Mechanosensing.
Degree: PhD, Physics, 2009, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:147/
► This dissertation explores two independent projects in biophysics. Part one focuses on the liquid crystalline phase transition of F-actin. The cytoskeletal protein actin can be…
(more)
▼ This dissertation explores two independent projects in
biophysics. Part one focuses on the liquid crystalline phase
transition of F-actin. The cytoskeletal protein actin can be found
in both an unordered isotropic state and an aligned nematic state,
and plays an important role in cell structure and motility. The
phase transition between these states is predicted to be a first
order transition, yet previous results have found it to be
continuous. We show here that the transition is truly first order
under the proper conditions of high concentration and short average
filament lengths. Under this regime, the solution spontaneously
separates into ordered domains in the shape of tactoidal droplets.
We explore the formation and growth mechanisms of the tactoids and
find that the system is only metastable. These findings help
clarify the phase separation and co-existence of actin, and may be
of relevance to its biological functions. Part two examines the
interaction of leukocytes with their substrate. We use
polyacrylamide gels to explore the role of the mechanical
environment in determining neutrophil behavior. We find that
neutrophils spread more and migrate slower but more persistently on
stiff substrates. Inhibition of phosphatidylinositol 3-kinase
(PI3K) removes this ability of the neutrophil to sense the
substrate stiffness, suggesting a role for PI3K in the mechanism
responsible for neutrophil mechanosensing. Furthermore, we find
that neutrophil force generation is strain limited and independent
of substrate stiffness within a limited range. The greatest forces
are found in the posterior of the cell, suggesting that the
neutrophil pushes, rather than pulls itself forward. Finally, we
use polarized T lymphocytes observed under total internal
reflection fluorescence (TIRF) microscopy to explore the
localization of integrins, the molecules responsible for adhesion
to the extracellular matrix. Active integrins are found localized
in the anterior of the cell during migration. These findings
elucidate the many complex interactions between the cell and
substrate, which drive leukocyte behavior. Future studies based on
these findings may lead to insights concerning the physiological
functions of leukocytes, and in particular how these functions are
regulated by the mechanical properties of the surrounding
tissues.
Advisors/Committee Members: Tang, Jay (director), Reichner, Jonathan (reader), Valles, James (reader).
Subjects/Keywords: actin
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
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APA (6th Edition):
Oakes, P. W. (2009). The Liquid Crystalline Transition of F-actin and Neutrophil
Mechanosensing. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:147/
Chicago Manual of Style (16th Edition):
Oakes, Patrick William. “The Liquid Crystalline Transition of F-actin and Neutrophil
Mechanosensing.” 2009. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:147/.
MLA Handbook (7th Edition):
Oakes, Patrick William. “The Liquid Crystalline Transition of F-actin and Neutrophil
Mechanosensing.” 2009. Web. 17 Jan 2021.
Vancouver:
Oakes PW. The Liquid Crystalline Transition of F-actin and Neutrophil
Mechanosensing. [Internet] [Doctoral dissertation]. Brown University; 2009. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:147/.
Council of Science Editors:
Oakes PW. The Liquid Crystalline Transition of F-actin and Neutrophil
Mechanosensing. [Doctoral Dissertation]. Brown University; 2009. Available from: https://repository.library.brown.edu/studio/item/bdr:147/
2.
Loosley, Alexander J.
The Mechanics of Cell Motility and a Unifying Theory for
Characterizing Directed Motion.
Degree: PhD, Physics, 2015, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:419363/
► This dissertation is split into two parts with the first focusing on characterizing cell motility, and the second focusing on linking cell motility to cell…
(more)
▼ This dissertation is split into two parts with the
first focusing on characterizing cell motility, and the second
focusing on linking cell motility to cell mechanics. Cellular
motility is routinely characterized by parameters such as migration
speed, tortuosity, and persistence time. However, measurements of
these parameters are not generally reproducible because their
numerical values depend on experimental sampling interval and
measurement error. In Part 1, we use random walk theory,
simulations, and experimental data to address the need for a metric
that quantifies the directionality of a migration path in a manner
that decouples from technical parameters. We call this novel metric
directionality time because it can be interpreted as the minimum
observation time required to determine that the migratory motion is
directed. Along with measures of migration speed and persistence,
we used the directionality time metric to determine the
directedness of chemotactic neutrophil migration paths as a
function of physiologically relevant substrate stiffnesses and
compositions. We find that engagement of the B2-integrin, CR3, is
required for the substrate stiffness dependent regulation of
neutrophil honing in 2D on fibronectin. In Part 2, we investigate
the role of cell mechanics in cell motility. As cells migrate, they
exert cytoskeletal driven contractile forces on their environment.
Using spring models with stick-slip adhesion, we are able to
predict how the mechanical properties and shape of the cell affect
its dynamics and traction forces. We then switch the focus back to
neutrophils and explore the relationship between neutrophil
contractile force, motility, and the biological response modifier
B-glucan, a substance that has shown promise as a clinic grade
therapeutic. Using live cell imaging and traction force microscopy
to measure neutrophil traction forces as a function of substrate
stiffness and β-glucan concentration, we report that
increasing the concentration of B-glucan leads to diminished
traction forces. Our findings indicate that biological response
modifiers may act through the modulation of cell mechanics and
motility. Further, we report an overall inverse correlation between
migration speed and mechanical output that is affected by B-glucan.
These data will be useful for modeling cell motility.
Advisors/Committee Members: Tang, Jay (Director), Reichner, Jonathan (Reader), Valles, James (Reader), Pelcovits, Robert (Reader).
Subjects/Keywords: cell motility
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Loosley, A. J. (2015). The Mechanics of Cell Motility and a Unifying Theory for
Characterizing Directed Motion. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:419363/
Chicago Manual of Style (16th Edition):
Loosley, Alexander J. “The Mechanics of Cell Motility and a Unifying Theory for
Characterizing Directed Motion.” 2015. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:419363/.
MLA Handbook (7th Edition):
Loosley, Alexander J. “The Mechanics of Cell Motility and a Unifying Theory for
Characterizing Directed Motion.” 2015. Web. 17 Jan 2021.
Vancouver:
Loosley AJ. The Mechanics of Cell Motility and a Unifying Theory for
Characterizing Directed Motion. [Internet] [Doctoral dissertation]. Brown University; 2015. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:419363/.
Council of Science Editors:
Loosley AJ. The Mechanics of Cell Motility and a Unifying Theory for
Characterizing Directed Motion. [Doctoral Dissertation]. Brown University; 2015. Available from: https://repository.library.brown.edu/studio/item/bdr:419363/
3.
Riolo, Matthew T.
HDAC6 restrict acetylated survivin nuclear export.
Degree: PhD, Pathobiology, 2012, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:297559/
► Survivin is an oncofetal protein expressed in most tumors. It is a unique member of the inhibitor of apoptosis family of proteins having a dual…
(more)
▼ Survivin is an oncofetal protein expressed in most
tumors. It is a unique member of the inhibitor of apoptosis family
of proteins having a dual function dependent on its subcellular
localization. Nuclear survivin is a critical member of the
chromosomal passenger complex essential for normal cell division,
while cytoplasmic survivin is antiapoptotic through indirect
inhibition of caspase activation. Critical to regulating survivin's
different functions are post-translational modifications such as
phosphporylation and ubiquitination, however a role for acetylation
has yet to be investigated. In this dissertation ten novel survivin
acetylation sites were identified and it was found that one in
particular, lysine 129, is an important regulator of survivin
subcellular localization. Using transfection assays, the
specificity of a novel survivin 129 acetylation antibody was
established and used to determine the histone deacetylase
responsible for survivin 129 deacetylation. First, treatment of
cancer cells with different chemical inhibitors revealed survivin
129 deacetylation occurs by a member of the class I/II HDAC family.
Multiple transfection assays identified HDAC6 as a primary
deacetylase of survivin at lysine 129 and experiments with HDAC6
mutant constructs indicated that domain II is essential for this
deacetylase activity. Subcellular fractionation revealed survivin
129 acetylation occurs in the nucleus, while HDAC6 resides in the
cytoplasm. However, transfection with CBP increased HDAC6
expression, nuclear localization, and interaction with survivin
suggesting a putative role of CBP in regulating HDAC6 function. In
ER+ breast cancer cells, treatment with estrogen increased survivin
expression, nuclear localization, and 129 acetylation, as well as
increased HDAC6 expression and nuclear localization. Together,
these results suggest a delicate regulation of survivin 129
acetylation/deacetylation mediated through alterations in growth
factor activated pathways. This dissertation identifies HDAC6 as a
primary deacetylase of survivin 129 acetylation and indicates a
novel mechanism of CBP mediated HDAC6 nuclear localization.
Further, results with estrogen treatment suggest survivin 129
acetylation is regulated through a growth factor mediated pathway
in ER+ breast cancer cells.
Advisors/Committee Members: Altura, Rachel (Director), Reichner, Jonathan (Reader), Chin, Eugene (Reader), Marshall, John (Reader), Fumihiko, Urano (Reader).
Subjects/Keywords: HDAC6
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Riolo, M. T. (2012). HDAC6 restrict acetylated survivin nuclear export. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297559/
Chicago Manual of Style (16th Edition):
Riolo, Matthew T. “HDAC6 restrict acetylated survivin nuclear export.” 2012. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:297559/.
MLA Handbook (7th Edition):
Riolo, Matthew T. “HDAC6 restrict acetylated survivin nuclear export.” 2012. Web. 17 Jan 2021.
Vancouver:
Riolo MT. HDAC6 restrict acetylated survivin nuclear export. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:297559/.
Council of Science Editors:
Riolo MT. HDAC6 restrict acetylated survivin nuclear export. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297559/
4.
Heflin, Katie Elizabeth.
The effects of extracellular matrix proteins and fungal
�glucan on CR3 structure, neutrophil migration and
mechanosensing.
Degree: PhD, Pathobiology, 2011, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:11296/
► Neutrophils are the body�s first cellular line of defense. Many of their functions are regulated by integrins through interactions with extracellular matrix (ECM). Insufficient activity…
(more)
▼ Neutrophils are the body�s first cellular line of
defense. Many of their functions are regulated by integrins through
interactions with extracellular matrix (ECM). Insufficient activity
of integrins results in infections and impaired healing, while
excessive activity leads to inflammation and tissue damage. The �
integrin CR3 has a unique lectin-like domain which binds
carbohydrates, including the fungal pathogen associated molecular
pattern �glucan. CR3 binding of ECM, carbohydrate or both
differentially regulates neutrophil function, though the mechanism
is not clearly understood.Using functional proteomic techniques, a
set of phosphopeptides that are regulated in a CR3-dependent manner
by �glucan were identified, confirming CR3 as a signaling receptor
for �glucan. Intracellular and extracellular changes in CR3
structure were assessed using fluorescence resonance energy
transfer reporters. While the ECM ligand fibrinogen (Fgn) alone
induced full activation of CR3 (headpiece extension and cytoplasmic
tail separation), �glucan alone or with Fgn stabilized an
intermediate conformation with moderate headpiece extension and
full cytoplasmic tail separation.Neutrophils migrate through
microenvironments with a range of mechanical properties, which can
be altered in disease. The migration dynamics (relative rate and
directionality) of neutrophils on surfaces of varying ECM protein
composition and stiffness were quantified and compared. The
mechanosensitivity of neutrophil migration is substrate-dependent,
with stiffness-dependent migration dynamics varying in response to
individual ECM proteins and mixtures. Inhibitor studies suggest
that the PI-3-kinase pathway is involved in regulating migration
dynamics under these conditions. Although migration on Fgn was
unaffected by surface stiffness, neutrophils treated with �glucan
showed mechanosensitive differences in their migration rate.This
dissertation explored the effects of �glucan on CR3 structure and
signaling and represents the first direct evidence of soluble
�glucan binding and affecting receptors on living cells. These
studies have also investigated the effects of �glucan on neutrophil
migration and mechanosensing across a variety of ECM
proteins.
Advisors/Committee Members: Reichner, Jonathan (Director), Hixson, Douglas (Reader), Salazar-Mather, Thais (Reader), Tang, Jay (Reader), Hammer, Daniel (Reader).
Subjects/Keywords: CR3
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Heflin, K. E. (2011). The effects of extracellular matrix proteins and fungal
�glucan on CR3 structure, neutrophil migration and
mechanosensing. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:11296/
Chicago Manual of Style (16th Edition):
Heflin, Katie Elizabeth. “The effects of extracellular matrix proteins and fungal
�glucan on CR3 structure, neutrophil migration and
mechanosensing.” 2011. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:11296/.
MLA Handbook (7th Edition):
Heflin, Katie Elizabeth. “The effects of extracellular matrix proteins and fungal
�glucan on CR3 structure, neutrophil migration and
mechanosensing.” 2011. Web. 17 Jan 2021.
Vancouver:
Heflin KE. The effects of extracellular matrix proteins and fungal
�glucan on CR3 structure, neutrophil migration and
mechanosensing. [Internet] [Doctoral dissertation]. Brown University; 2011. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:11296/.
Council of Science Editors:
Heflin KE. The effects of extracellular matrix proteins and fungal
�glucan on CR3 structure, neutrophil migration and
mechanosensing. [Doctoral Dissertation]. Brown University; 2011. Available from: https://repository.library.brown.edu/studio/item/bdr:11296/
5.
Chung, Waihong.
MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS
TRANSGENIC MICE.
Degree: PhD, Pathobiology, 2015, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:419352/
► Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer death in the United States. Chronic…
(more)
▼ Hepatocellular carcinoma (HCC) is the fifth most
common cancer in the world and the third leading cause of cancer
death in the United States. Chronic hepatitis B virus (HBV)
infection is the leading cause of this devastating disease,
accounting for 59% of HCCs in developing countries. The oncogenic
properties of HBV have been linked to transactivation of cellular
signaling pathways by a small viral protein – hepatitis B virus X
protein (HBx). It has been shown that HBx can upregulate the
insulin/insulin-like growth factor (IGF) pathway, the Wnt/β-catenin
pathway, and the Notch pathway in vitro. Aberrant activation of
these signaling pathways is thought to play a crucial role in
hepatocarcinogenesis. Single transgenic animal models that
overexpress HBx or insulin receptor substrate-1 (IRS-1) have been
previously created, but failed to develop tumors. The goal of this
research project is to create an animal model for HBV-mediated HCC
that accurately recapitulates the dysregulated signal transduction
events observed in the human disease. We hypothesize that
simultaneous, constitutive expression of HBx and IRS-1 is necessary
and sufficient to cause malignant transformation in normal livers.
Moreover, we postulate that overexpression of the two transgenes
results in sustained, synergistic activation of insulin/IGF,
Wnt/β-catenin, and Notch via an elaborate crosstalk and feedback
network that exists among the three pathways. Finally, we
demonstrates that aspartyl-(asparaginyl)-β-hydroxylase (AAH), a
transmembrane protein that connects the insulin/IGF signaling
pathway to the Notch signaling pathway, is a clinically useful
prognostic biomarker for advanced HCCs as well as a highly
sensitive diagnostic biomarker for pancreatic exocrine tumors and
colorectal tumors.
Advisors/Committee Members: Wands, Jack (Director), Bordsky, Alexander (Reader), Reichner, Jonathan (Reader), Resnick, Murrary (Reader).
Subjects/Keywords: Hepatocellular
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Chung, W. (2015). MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS
TRANSGENIC MICE. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:419352/
Chicago Manual of Style (16th Edition):
Chung, Waihong. “MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS
TRANSGENIC MICE.” 2015. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:419352/.
MLA Handbook (7th Edition):
Chung, Waihong. “MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS
TRANSGENIC MICE.” 2015. Web. 17 Jan 2021.
Vancouver:
Chung W. MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS
TRANSGENIC MICE. [Internet] [Doctoral dissertation]. Brown University; 2015. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:419352/.
Council of Science Editors:
Chung W. MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS
TRANSGENIC MICE. [Doctoral Dissertation]. Brown University; 2015. Available from: https://repository.library.brown.edu/studio/item/bdr:419352/
6.
Magruder, Hilary.
Signaling Effectors Required for G Protein-Coupled Estrogen
Receptor-, GPER, Induced Events Associated with Breast Cancer
Progression.
Degree: PhD, Pathobiology, 2014, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:386260/
► Stimulation of estrogen receptor (ER)-negative human breast cancer cells with 17β-estradiol (E2β) results in fibronectin (FN) matrix assembly and transactivation of the epidermal growth factor…
(more)
▼ Stimulation of estrogen receptor (ER)-negative human
breast cancer cells with 17β-estradiol (E2β) results in fibronectin
(FN) matrix assembly and transactivation of the epidermal growth
factor receptor (EGFR) via the G protein-coupled estrogen receptor
(GPER). This mechanism of action results in the recruitment of
FN-engaged integrin α5β1 to fibrillar adhesions and the formation
of integrin α5β1-Shc adaptor protein complexes. Here, we show that
GPER stimulation of murine 4T1 or human SKBR3 breast cancer cells
promotes the formation of focal adhesions, actin stress fibers, and
results in increased cellular adhesion and haptotaxis on FN, but
not collagen. These actions are also induced by the xenoestrogen,
bisphenol A, and the ER antagonist, ICI 182, 780, but not the
inactive stereoisomer, 17α-estradiol (E2α). In addition, we show
that GPER stimulation of breast cancer cells allows for
FN-dependent, anchorage-independent growth and FN fibril formation
in hanging drop assays, indicating that these GPER-mediated actions
occur independently of adhesion to solid substrata. Furthermore,
stable expression of Shc mutant Y317F lacking its primary tyrosyl
phosphorylation site disrupts E2β-induced focal adhesion and actin
stress fiber formation, and abolishes E2β-enhanced haptotaxis on FN
and anchorage-dependent growth. We also show that overexpression of
a phosphatase, PTPN12, known to interact with Shc inhibits focal
adhesion and FN fibril formation, adhesion and haptotaxis on FN,
and anchorage independent growth. Moreover, PTPN12 knockdown
positively influences these events associated with cellular
survival. Collectively, these data demonstrate that E2β action via
GPER enhances cellular adhesivity and FN matrix assembly and allows
for anchorage-independent growth, cellular events that may allow
for cellular survival and tumor progression.
Advisors/Committee Members: Filardo, Edward (Director), Reichner, Jonathan (Reader), Freiman, Richard (Reader), Yang, Wentian (Reader), Prossnitz, Eric (Reader).
Subjects/Keywords: estrogen receptor (ER)
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Magruder, H. (2014). Signaling Effectors Required for G Protein-Coupled Estrogen
Receptor-, GPER, Induced Events Associated with Breast Cancer
Progression. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:386260/
Chicago Manual of Style (16th Edition):
Magruder, Hilary. “Signaling Effectors Required for G Protein-Coupled Estrogen
Receptor-, GPER, Induced Events Associated with Breast Cancer
Progression.” 2014. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:386260/.
MLA Handbook (7th Edition):
Magruder, Hilary. “Signaling Effectors Required for G Protein-Coupled Estrogen
Receptor-, GPER, Induced Events Associated with Breast Cancer
Progression.” 2014. Web. 17 Jan 2021.
Vancouver:
Magruder H. Signaling Effectors Required for G Protein-Coupled Estrogen
Receptor-, GPER, Induced Events Associated with Breast Cancer
Progression. [Internet] [Doctoral dissertation]. Brown University; 2014. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:386260/.
Council of Science Editors:
Magruder H. Signaling Effectors Required for G Protein-Coupled Estrogen
Receptor-, GPER, Induced Events Associated with Breast Cancer
Progression. [Doctoral Dissertation]. Brown University; 2014. Available from: https://repository.library.brown.edu/studio/item/bdr:386260/
7.
Biron, Bethany.
The Role of Peptidyl arginine deiminase, type IV (PAD4) in
the Pathology of Shock/Sepsis.
Degree: Pathobiology, 2017, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:733274/
► Sepsis is a life threatening condition that elicits a dysregulated and damaging immune response, which in turn leads to tissue damage and Multiple Organ Dysfunction…
(more)
▼ Sepsis is a life threatening condition that elicits a
dysregulated and damaging immune response, which in turn leads to
tissue damage and Multiple Organ Dysfunction (MOD). Critically ill
patients that have suffered from trauma, complex surgery,
gastrointestinal bleeding, obstetrical bleeding, etc., have an
increased risk of developing sepsis, which may progress to Acute
Respiratory Distress Syndrome (ARDS), leading in turn to an
increase in mortality. Neutrophils are thought to play a role in
the immune dysfunction seen in both shock and sepsis, and have been
implicated in causing bystander tissue damage and organ
dysfunction. Neutrophil extracellular traps (NETs) are large webs
of decondensed chromatin coated with antimicrobial proteins that
are released into the extracellular space. They serve as a novel
effector function, regulated by the enzyme Peptidyl arginine
deiminase, type IV (PAD4). NETs have been identified as an
important aspect of innate immunity, but have also been linked to
excessive inflammation and tissue damage. Their role in sepsis and
shock/sepsis, however, is poorly understood. This dissertation
examines how PAD4 (an enzyme central to NET formation) plays a role
in the pathology of sepsis. It also examines whether a
predispositional insult, such as severe shock antecedent to septic
challenge, is affected this enzyme. Here we demonstrate that
inhibition of PAD4 reduces mortality seen in a mouse polymicrobial
sepsis model (CLP), as well as in a mouse model of hemorrhagic
shock and sepsis (Hem/CLP). Clinically we showed that there is
evidence of increased NET activity in septic patients. Together,
this implies that PAD4-mediated NET formation contributes to the
morbidity and mortality associated with sepsis and shock/sepsis,
and that PAD4 merits further exploration as a possible therapeutic
target against the damaging pro-inflammatory response seen in
polymicrobial sepsis and indirect ARDS.
Advisors/Committee Members: Ayala, Alfred (Advisor), Reichner, Jonathan (Reader), Lefort, Craig (Reader), Heffernan, Daithi (Reader), Levy, Bruce (Reader).
Subjects/Keywords: Cellular immunity
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Biron, B. (2017). The Role of Peptidyl arginine deiminase, type IV (PAD4) in
the Pathology of Shock/Sepsis. (Thesis). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:733274/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Biron, Bethany. “The Role of Peptidyl arginine deiminase, type IV (PAD4) in
the Pathology of Shock/Sepsis.” 2017. Thesis, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:733274/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Biron, Bethany. “The Role of Peptidyl arginine deiminase, type IV (PAD4) in
the Pathology of Shock/Sepsis.” 2017. Web. 17 Jan 2021.
Vancouver:
Biron B. The Role of Peptidyl arginine deiminase, type IV (PAD4) in
the Pathology of Shock/Sepsis. [Internet] [Thesis]. Brown University; 2017. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:733274/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Biron B. The Role of Peptidyl arginine deiminase, type IV (PAD4) in
the Pathology of Shock/Sepsis. [Thesis]. Brown University; 2017. Available from: https://repository.library.brown.edu/studio/item/bdr:733274/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
8.
Cao, Cong.
The role of inhibitory heterotrimeric G proteins in Receptor
Tyrosine Kinase function and identification of defective TrkB
signaling in Angelman Syndrome.
Degree: PhD, Pathobiology, 2011, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:11272/
► The Epidermal growth factor (EGF) receptor (EGFR), tropomyosin-receptor kinase (Trk) and other receptor tyrosine kinase (RTK) family members play pivotal roles in regulating the normal…
(more)
▼ The Epidermal growth factor (EGF) receptor (EGFR),
tropomyosin-receptor kinase (Trk) and other receptor tyrosine
kinase (RTK) family members play pivotal roles in regulating the
normal biological process and malignant transformation. They
activate downstream transduction signal transduction cascades, that
include the phosphoinositide 3-kinase (PI3K) /AKT/ mammalian target
of rapamycin complex 1 (mTORC1) and mitogen-activated protein
kinase (MAPK) pathways, which are vital for cell proliferation,
growth, migration and survival. However, it is still not entirely
understood how the RTK transduces signals to PI3K/AKT/ mTORC1 and
MAPK. The first part of this thesis focuses on the role of
heterotrimeric G protein alpha subunits, Gai1 and Gai3, in this
process. We identify an association of Gai proteins with the RTK
and the adaptor protein Gab1 (Grb2 associated bind 1). This
interaction is required for subsequent Gab1 phosphorylation, and
downstream activation of the AKT-mTOR and the MAPK pathways in
response to RTK ligands, including EGF and brain-derived
neurotrophic factor (BDNF). This study demonstrates a novel role
between Gai proteins, traditionally known as components in
G-protein coupled receptor (GPCR) signaling, and RTK signaling.
Angelman Syndrome (AS) is a neurological disorder caused by a loss
of maternal expression of the ubiquitin E3 ligase gene UBE3A.
Common symptoms of AS include developmental delay, mental
retardation, excessive inappropriate laughter, movement ataxia,
seizures, and lack of speech. The precise molecular mechanisms
which cause the symptoms of Angelman Syndrome, however, are still
not completely understood. We discovered that BDNF/TrkB signaling
is deficient in Angelman Syndrome (AS) mice, providing a possible
explanation for LTP (long-term potentiation) loss and other
symptoms associated with Angelman Syndrome. CN 2097, a newly
synthesized cyclic peptide designed to target the PDZ domains of
the PSD-95, rescued BDNF signaling and LTP in AS mice. PSD-95 forms
a complex with TrkB after BDNF treatment and CN 2097 increased this
association to enhance PI3K/AKT and CaMKII signaling. This study
suggests that CN 2097 may represent a new therapeutic option for
treating this disease.
Advisors/Committee Members: Marshall, John (Director), Bowen, Wayne (Reader), Green, William (Reader), Biron, Christine (Reader), Reichner, Jonathan (Reader).
Subjects/Keywords: receptor tyrosine kinase signaling
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
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APA (6th Edition):
Cao, C. (2011). The role of inhibitory heterotrimeric G proteins in Receptor
Tyrosine Kinase function and identification of defective TrkB
signaling in Angelman Syndrome. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:11272/
Chicago Manual of Style (16th Edition):
Cao, Cong. “The role of inhibitory heterotrimeric G proteins in Receptor
Tyrosine Kinase function and identification of defective TrkB
signaling in Angelman Syndrome.” 2011. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:11272/.
MLA Handbook (7th Edition):
Cao, Cong. “The role of inhibitory heterotrimeric G proteins in Receptor
Tyrosine Kinase function and identification of defective TrkB
signaling in Angelman Syndrome.” 2011. Web. 17 Jan 2021.
Vancouver:
Cao C. The role of inhibitory heterotrimeric G proteins in Receptor
Tyrosine Kinase function and identification of defective TrkB
signaling in Angelman Syndrome. [Internet] [Doctoral dissertation]. Brown University; 2011. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:11272/.
Council of Science Editors:
Cao C. The role of inhibitory heterotrimeric G proteins in Receptor
Tyrosine Kinase function and identification of defective TrkB
signaling in Angelman Syndrome. [Doctoral Dissertation]. Brown University; 2011. Available from: https://repository.library.brown.edu/studio/item/bdr:11272/
9.
Linden, Jennifer R.
Galectin-3 and Candidiasis: Its Role in Human Neutrophil
Phagocytosis and in Disseminated Disease.
Degree: PhD, Pathobiology, 2012, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:297569/
► Candida albicans causes the majority of invasive candidiasis in immunocompromised adults while Candida parapsilosis is a leading cause of neonatal candidiasis. While considerable study has…
(more)
▼ Candida albicans causes the majority of invasive
candidiasis in immunocompromised adults while Candida parapsilosis
is a leading cause of neonatal candidiasis. While considerable
study has focused on how the immune system recognizes and responds
to C. albicans, little is known about host interactions with C.
parapsilosis. This study investigated the human neutrophil response
to these two species. Human neutrophils phagocytosed C.
parapsilosis much more efficiently than C. albicans yeast and
exhibited distinctly different morphological responses. Subsequent
experiments focused on the identification of the fungal ligand and
neutrophil receptors involved in efficient phagocytosis of C.
parapsilosis. To identify the fungal ligand involved, neutrophils
were treated with soluble components of the fungal cell wall
including β-glucan, chitin and mannan extracted from C.
parapsilosis, C. albicans and S. cerevisiae. Mannan extracted from
C. parapsilosis inhibited phagocytosis of whole C. parapsilosis
yeast, indicating that C. parapsilosis mannan may be the ligand
initiating phagocytosis. To identify the neutrophil receptor
involved in efficient phagocytosis, neutrophils were treated with
blocking antibodies against dectin-1, TLR2, TLR4, TLR6, CR3 and
galectin-3. Only treatment with the galectin-3 blocking antibody
inhibited phagocytosis of C. parapsilosis yeast, but not C.
albicans yeast. Treatment with the galectin-3 antibody also
inhibited efficient phagocytosis of C. albicans hyphae. The
majority of neutrophil galectin-3 was expressed intracellularly but
was secreted when treated with C. parapsilosis mannan. When
neutrophils were treated with exogenous galectin-3, phagocytosis of
both C. albicans and C. parapsilosis yeast increased. Exposure of
neutrophils to C. parapsilosis increased phagocytosis of C.
albicans yeast and was inhibited by galectin-3 blocking antibody.
Taken together, these data indicate that galectin-3 secreted from
neutrophils may act as a proinflammatory autocrine/paracrine signal
in neutrophil phagocytosis. Mice deficient in galectin-3 were more
susceptible to infection with either C. parapsilosis or C.
albicans. Interestingly, serum galectin-3 levels were lower in
human newborns when compared to adults. These data suggest that
galectin-3 has a unique role in neutrophil recognition of C.
parapsilosis distinct from C. albicans and protects against
disseminated candidiasis.
Advisors/Committee Members: Bliss, Joseph (Director), Bennett, Richard (Reader), Shaw, Sunil (Reader), Reichner, Jonathan (Reader), Levitz, Stuart (Reader).
Subjects/Keywords: Candida parapsilosis
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Linden, J. R. (2012). Galectin-3 and Candidiasis: Its Role in Human Neutrophil
Phagocytosis and in Disseminated Disease. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297569/
Chicago Manual of Style (16th Edition):
Linden, Jennifer R. “Galectin-3 and Candidiasis: Its Role in Human Neutrophil
Phagocytosis and in Disseminated Disease.” 2012. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:297569/.
MLA Handbook (7th Edition):
Linden, Jennifer R. “Galectin-3 and Candidiasis: Its Role in Human Neutrophil
Phagocytosis and in Disseminated Disease.” 2012. Web. 17 Jan 2021.
Vancouver:
Linden JR. Galectin-3 and Candidiasis: Its Role in Human Neutrophil
Phagocytosis and in Disseminated Disease. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:297569/.
Council of Science Editors:
Linden JR. Galectin-3 and Candidiasis: Its Role in Human Neutrophil
Phagocytosis and in Disseminated Disease. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297569/
10.
Toyjanova, Jennet.
The Effect of Confinement on Neutrophil Force
Generation.
Degree: PhD, Mechanics of Solids, 2015, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:419365/
► Generation of forces is essential for the migration of neutrophils to the sites of infection or injury. The mechanical properties and local confinement of the…
(more)
▼ Generation of forces is essential for the migration of
neutrophils to the sites of infection or injury. The mechanical
properties and local confinement of the surrounding
microenvironment play a significant role in regulating these
forces. However, it is challenging to decouple each of these
features experimentally without inherently changing the
microstructure of the cell environment. Presented here is an
experimental method that is used to isolate confinement and
substrate stiffness as single variables in the neutrophil
environment. Using a combination of fast iterative digital volume
correlation and traction force microscopy techniques, this
dissertation demonstrates that neutrophils induce finite
displacements on their surroundings. Furthermore, the findings show
that neutrophil-generated forces are highly affected by confinement
and stiffness of their microenvironment.
Advisors/Committee Members: Franck, Christian (Director), Bower, Allan (Reader), Hammer, Daniel (Reader), Kim, Kyung-Suk (Reader), Reichner, Jonathan (Reader).
Subjects/Keywords: cell mechanics
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Toyjanova, J. (2015). The Effect of Confinement on Neutrophil Force
Generation. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:419365/
Chicago Manual of Style (16th Edition):
Toyjanova, Jennet. “The Effect of Confinement on Neutrophil Force
Generation.” 2015. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:419365/.
MLA Handbook (7th Edition):
Toyjanova, Jennet. “The Effect of Confinement on Neutrophil Force
Generation.” 2015. Web. 17 Jan 2021.
Vancouver:
Toyjanova J. The Effect of Confinement on Neutrophil Force
Generation. [Internet] [Doctoral dissertation]. Brown University; 2015. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:419365/.
Council of Science Editors:
Toyjanova J. The Effect of Confinement on Neutrophil Force
Generation. [Doctoral Dissertation]. Brown University; 2015. Available from: https://repository.library.brown.edu/studio/item/bdr:419365/
11.
Newsome, Courtni Takiyah.
Effects of Beta-Glucan on Sepsis and Endotoxemia.
Degree: PhD, Pathobiology, 2010, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:11086/
► Beta-glucans are glucose polymers found of the fungal cell wall. Beta-glucans have immunological effects and can stimulate innate immune cells. Priming immune cell function can…
(more)
▼ Beta-glucans are glucose polymers found of the fungal
cell wall. Beta-glucans have immunological effects and can
stimulate innate immune cells. Priming immune cell function can be
of clinical benefit, however, it results in the overproduction of
pro-inflammatory cytokines which may be detrimental to the patient.
The soluble, beta-glucan PGG-glucan, which was prepared from
Saccharomyces cerevisiae, primes antimicrobial functions without
stimulating cytokines. The prophylactic effects of beta-glucan have
been evaluated, however, it is unknown if PGG-beta-glucan can be
beneficial when given to a patient or an experimental animal that
is already infected. Our first aim was to evaluate the effect of
PGG-glucan on the mortality of and cytokine production and
bacteremia in septic mice induced by cecal ligation and puncture
(CLP) when administered after the onset of infection. These results
indicate that PGG-glucan given 1 hour after CLP enhanced 10-day
survival in female mice but not in male mice. Elevated IL-6 levels
predicted mortality, however, differences in IL-6 values determined
to predict 100% mortality between the sexes existed. PGG-glucan did
not increase 10-day survival in ovariectomized female mice or in
ovariectomized female mice given a dose of estrogen, indicating
that hormones play a role in protection mediated by PGG-glucan, and
that estrogen is necessary, but not sufficient for protection.
PGG-glucan reduced IL-6 and IL-10 levels in male and female mice.
Next, we evaluated the effect of PGG-glucan pretreatment on the
LPS-induced TNF production in vivo. The results indicate that
PGG-glucan pretreatment for 96 hours prior to LPS stimulation
reduced TNF, IL-6 and IL-10 production in 4-5 month old male mice,
but not in 6-8 week old male mice. The results also indicate that
PGG-glucan attenuated TNF production in 20 month old female mice,
but not in 6-8 week old or 4-5 month old female mice. PGG-glucan
could be developed as a therapeutic agent to potentiate immune cell
functions of patients without inducing the negative side effects of
cytokine production.
Advisors/Committee Members: Reichner, Jonathan (Director), Ayala, Alfred (Reader), Moss, Steven (Reader), Sharma, Surendra (Reader), Sherwood, Edrward (Reader).
Subjects/Keywords: beta-glucan
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Newsome, C. T. (2010). Effects of Beta-Glucan on Sepsis and Endotoxemia. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:11086/
Chicago Manual of Style (16th Edition):
Newsome, Courtni Takiyah. “Effects of Beta-Glucan on Sepsis and Endotoxemia.” 2010. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:11086/.
MLA Handbook (7th Edition):
Newsome, Courtni Takiyah. “Effects of Beta-Glucan on Sepsis and Endotoxemia.” 2010. Web. 17 Jan 2021.
Vancouver:
Newsome CT. Effects of Beta-Glucan on Sepsis and Endotoxemia. [Internet] [Doctoral dissertation]. Brown University; 2010. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:11086/.
Council of Science Editors:
Newsome CT. Effects of Beta-Glucan on Sepsis and Endotoxemia. [Doctoral Dissertation]. Brown University; 2010. Available from: https://repository.library.brown.edu/studio/item/bdr:11086/
12.
Nevers, Tania A.
Inflammatory and dysfunctional regulatory T cells in adverse
pregnancy outcomes.
Degree: PhD, Pathobiology, 2012, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:297562/
► The etiologies for adverse pregnancy outcomes such as recurrent spontaneous abortion, preeclampsia, preterm birth and gestational diabetes mellitus (GDM) are multi-factorial and remain poorly understood.…
(more)
▼ The etiologies for adverse pregnancy outcomes such as
recurrent spontaneous abortion, preeclampsia, preterm birth and
gestational diabetes mellitus (GDM) are multi-factorial and remain
poorly understood. The main reasons for enigmatic state of adverse
pregnancy outcomes can be assigned to lack of well defined animal
models in response to inflammatory triggers and early pregnancy
predictive assays and biomarkers. However, these pregnancy
complications have a common
contributor in inflammation at the
maternal-fetal interface. In normal pregnancy, a state of immune
tolerance is choreographed involving pro- and anti-inflammatory
signals. Regulatory T cells (Tregs) have acquired a premier role in
regulating immune tolerance systemically and at the maternal-fetal
interface. Here we focus on Tregs for their phenotypic and
functional dysregulation in mouse and human models of pregnancy
complications. Importantly, we invoke the role of IL-10, a
signature cytokine of Tregs, and human chorionic gonadotropin (hCG)
in maintaining normal pregnancy. Our overarching hypothesis is that
uterine regulatory T cells are dysfunctional in adverse pregnancies
associated with infection and /or inflammation and may be
normalized by IL-10 and hCG.
This work explores dysregulation of uterine Tregs by
utilizing mouse models of adverse pregnancies, human peripheral
blood Tregs and sera from normal pregnancy, preeclampsia and
gestational diabetes. In Chapter 2, we show that uterine regulatory
T cells amplify and acquire an inflammatory phenotype in response
to the TLR-3 agonist and cause pregnancy demise in IL-10-/- and
wild-type (WT) mice. In Chapter 3, we present for the first time
that peripheral blood Tregs from GDM patients present an
“exhausted” phenotype and express the programmed death receptor
(PD-1). Tregs from GDM lose CD25 and Foxp3 expression upon
overnight culturing which can be partially rescued by TGF-β, IL-2,
or PD-1 blockade. This phenotype was not observed in Tregs from
normal pregnancy. In Chapter 4, we describe that hCG produced in
preeclampsia is inactive and does not support angiogenesis and
recruitment of Tregs to the uterus in the “humanized” mouse model
of preeclampsia. Collectively, the results presented in this thesis
provide novel pathways by which regulatory T cells can present
themselves as foes of normal pregnancy.
Advisors/Committee Members: Sharma, Surendra (Director), Ayala, alfred (Reader), Fast, Loren (Reader), Reichner, Jonathan (Reader), Golos, Thaddeus (Reader).
Subjects/Keywords: Regulatory T cells
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Nevers, T. A. (2012). Inflammatory and dysfunctional regulatory T cells in adverse
pregnancy outcomes. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297562/
Chicago Manual of Style (16th Edition):
Nevers, Tania A. “Inflammatory and dysfunctional regulatory T cells in adverse
pregnancy outcomes.” 2012. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:297562/.
MLA Handbook (7th Edition):
Nevers, Tania A. “Inflammatory and dysfunctional regulatory T cells in adverse
pregnancy outcomes.” 2012. Web. 17 Jan 2021.
Vancouver:
Nevers TA. Inflammatory and dysfunctional regulatory T cells in adverse
pregnancy outcomes. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:297562/.
Council of Science Editors:
Nevers TA. Inflammatory and dysfunctional regulatory T cells in adverse
pregnancy outcomes. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297562/
13.
Valm, Alex Mihkel.
Combinatorial Labeling and Spectral Imaging (CLASI): A novel
microscopy method for the systems-level analysis of biological
structure and its application to the study of human oral microbial
community organization.
Degree: PhD, Pathobiology, 2012, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:297560/
► Just as the phenotypically different cells that make up multicellular organisms are distributed in tissues with structures that embody specific functions, microbial cells with different…
(more)
▼ Just as the phenotypically different cells that make
up multicellular organisms are distributed in tissues with
structures that embody specific functions, microbial cells with
different metabolic functions form unique spatial structures and
coordinate their activities as multicellular units, e.g. biofilms.
Fundamentally, microbial communities differ from eukaryotic tissues
because their cellular constituents may be genetically distinct; in
fact, up to hundreds of different species may be present in a
single biofilm. Any number of probes may be designed to identify
the different species present in a community; however, the ability
to unambiguously distinguish more than a few different labels in a
single fluorescence image has been severely hampered by the
excitation cross talk and signal bleed-through of fluorophores with
highly overlapping emission spectra.
Reported in this thesis is a fluorescence labeling, imaging,
and analysis method to greatly expand the number of identifiable
labels in a single image, which we call Combinatorial Labeling and
Spectral Imaging (CLASI). Application of our CLASI technique to
human dental plaque using fluorescence in situ hybridization (FISH)
enabled the first quantitative analysis of the spatial distribution
of 15 different taxa of microbes in a biofilm. Proximity analysis
was used to determine the frequency of inter- and intrataxon
cell-to-cell associations, which revealed statistically significant
intertaxon pairings. Cells of the genera Prevotella and Actinomyces
showed the most interspecies associations, suggesting a central
role for these genera in establishing and maintaining biofilm
complexity. In a proof-of-principle experiment, we further
demonstrate that we can distinguish 120 differently labeled E. coli
in a mixture labeled with binary combinations of 16 fluorophores
using a novel linear unmixing algorithm constrained to identify
specific combinations of fluorophores. Our results provide an
initial systems-level structural analysis of biofilm organization
and we further believe that the CLASI approach will be useful for
the architectural analysis of many complex molecular structures
within cells.
Advisors/Committee Members: Oldenbourg, Rudolf (Director), Borisy, Gary (Director), Atwood, Walter (Reader), Reichner, Jonathan (Reader), Danuser, Gaudenz (Reader).
Subjects/Keywords: fluorescence imaging
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Valm, A. M. (2012). Combinatorial Labeling and Spectral Imaging (CLASI): A novel
microscopy method for the systems-level analysis of biological
structure and its application to the study of human oral microbial
community organization. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297560/
Chicago Manual of Style (16th Edition):
Valm, Alex Mihkel. “Combinatorial Labeling and Spectral Imaging (CLASI): A novel
microscopy method for the systems-level analysis of biological
structure and its application to the study of human oral microbial
community organization.” 2012. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:297560/.
MLA Handbook (7th Edition):
Valm, Alex Mihkel. “Combinatorial Labeling and Spectral Imaging (CLASI): A novel
microscopy method for the systems-level analysis of biological
structure and its application to the study of human oral microbial
community organization.” 2012. Web. 17 Jan 2021.
Vancouver:
Valm AM. Combinatorial Labeling and Spectral Imaging (CLASI): A novel
microscopy method for the systems-level analysis of biological
structure and its application to the study of human oral microbial
community organization. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:297560/.
Council of Science Editors:
Valm AM. Combinatorial Labeling and Spectral Imaging (CLASI): A novel
microscopy method for the systems-level analysis of biological
structure and its application to the study of human oral microbial
community organization. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297560/
14.
Jiz, Mario Antonio II L.
Vaccine Development in Schistosomiasis japonica: Paramyosin
As a Leading Candidate.
Degree: PhD, Division of Biology and Medicine.
Pathobiology, 2009, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:175/
► Schistosomiasis is a chronic debilitating disease caused by helminths of the genus Schistosoma, and currently affecting millions in the developing world. Treatment with Praziquantel has…
(more)
▼ Schistosomiasis is a chronic debilitating disease
caused by helminths of the genus Schistosoma, and currently
affecting millions in the developing world. Treatment with
Praziquantel has reduced severe morbidities, however reinfection is
common and subtle morbidities persist. Alternative control
strategies such as vaccine-linked chemotherapy show great promise
and warrant further development. This thesis describes vaccine
development in schistosomiasis japonica, in conjunction with our
recently concluded treatment-reinfection study of a Schistosoma
japonicum-infected cohort in Leyte, Philippines (N=553). The
promising vaccine candidate paramyosin remains under-evaluated due
to challenges in large-scale recombinant production, and we address
this need with a robust process to express and purify S. japonicum
paramyosin (rSj97). Pilot scale production yielded 22.4 mg of
>95% pure rSj97, with functional binding and structural
properties similar to native paramyosin. Sera collected from the
cohort one month post-treatment were analyzed for isotype-specific
(IgA, IgE, IgG1, IgG4, total IgG) antibody responses to a panel of
schistosome antigens (SWAP, rSj97, rSj67, rSj22) using a
multiplexed bead-based assay. Repeated measures regression analysis
with reinfection data up to 12 months post-treatment showed that
IgE responses to rSj97 solely predicted resistance to reinfection
(p=0.018), while IgG4 responses to all antigens associated with
susceptibility, after adjusting for potential confounders. In
combined IgE and IgG4 analysis to rSj97, individuals with only IgE
responses had a 77% lower intensity of reinfection at 12 months
post-treatment (p=0.016) compared to individuals with IgG4 but not
IgE. Immunoscreening of an S. japonicum expression library for
clones differentially recognized by the resistant but not
susceptible subpopulation identified a novel vaccine candidate,
Sj6-8. Sj6-8 was expressed in E. coli, and a similar repeated
measures analysis demonstrated that IgE responses to rSj6-8 was
marginally associated with resistance (p=0.065), predicting a 63%
lower intensity of reinfection at 12 months post-treatment.
Overall, this thesis further supports paramyosin as a leading
vaccine candidate for schistosomiasis japonica, and our development
of a pilot scale production process for rSj97 paves the way for
further pre-clinical and eventual clinical testing of this
promising vaccine candidate.
Advisors/Committee Members: Kurtis, Jonathan (director), Knopf, Paul (reader), Friedman, Jennifer (reader), McGarvey, Stephen (reader), Reichner, Jonathan (reader).
Subjects/Keywords: vaccine
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Jiz, M. A. I. L. (2009). Vaccine Development in Schistosomiasis japonica: Paramyosin
As a Leading Candidate. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:175/
Chicago Manual of Style (16th Edition):
Jiz, Mario Antonio II L. “Vaccine Development in Schistosomiasis japonica: Paramyosin
As a Leading Candidate.” 2009. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:175/.
MLA Handbook (7th Edition):
Jiz, Mario Antonio II L. “Vaccine Development in Schistosomiasis japonica: Paramyosin
As a Leading Candidate.” 2009. Web. 17 Jan 2021.
Vancouver:
Jiz MAIL. Vaccine Development in Schistosomiasis japonica: Paramyosin
As a Leading Candidate. [Internet] [Doctoral dissertation]. Brown University; 2009. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:175/.
Council of Science Editors:
Jiz MAIL. Vaccine Development in Schistosomiasis japonica: Paramyosin
As a Leading Candidate. [Doctoral Dissertation]. Brown University; 2009. Available from: https://repository.library.brown.edu/studio/item/bdr:175/
15.
Brown, Caitlin Westberg.
Notch3 promotes anoikis resistance via expression of col4α2
in epithelial ovarian cancer.
Degree: PhD, Pathobiology, 2014, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:386266/
► Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The five-year survival rate of women diagnosed with stage IV high-grade serous epithelial ovarian cancer…
(more)
▼ Epithelial ovarian cancer (EOC) is the most lethal
gynecologic malignancy. The five-year survival rate of women
diagnosed with stage IV high-grade serous epithelial ovarian cancer
is 19% (NCI). A strong tendency towards genomic instability,
chemoresistance and a late diagnosis all contribute to the poor
overall survival rate. Despite the development of new
chemotherapeutics and novel delivery methods, this rate has not
changed significantly since the 1970s, indicating a need for new
therapeutic targets. The Notch signaling pathway has been
implicated in tumorigenesis and cancer progression in several
cancer types. However, the role of Notch signaling has also been
shown to be highly context-dependent. The mechanism by which Notch3
promotes dissemination of epithelial ovarian tumors is currently an
active area of study. The studies presented in this thesis
characterize an in vitro cell model of the role of Notch3 promoting
metastasis in EOC. This model was used to establish that Notch3
promotes invasion in the IGROV-1 cell line but does not appear to
play a significant role in regulating migration, resistance to
oxaliplatin or cell cycle alterations. Additionally, we found that
Notch3 promotes anoikis resistance. We report a positive role for
focal adhesion kinase as well as the downstream signaling kinases
Akt and Erk 1/2 in promoting the anchorage-independent growth
ovarian cancer cells. mRNA and protein levels of col4α2 are reduced
when Notch3 levels are decreased and exogenous collagen IV
supplementation can largely reverse the anoikis sensitivity.
Reduction of col4α2 expression by siRNA induces cell death. High
Notch3 expression levels correlate with higher col4α2 expression in
human ovarian tumor samples. Our data thus expand on previous
findings and highlight type IV collagen as a novel potential
therapeutic target for metastatic epithelial ovarian
cancer.
Advisors/Committee Members: Freiman, Richard (Director), Boekelheide, Kim (Reader), Reichner, Jonathan (Reader), Zhitkovich, Anatoly (Reader), Zhang, Hong (Reader).
Subjects/Keywords: epithelial ovarian cancer
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Brown, C. W. (2014). Notch3 promotes anoikis resistance via expression of col4α2
in epithelial ovarian cancer. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:386266/
Chicago Manual of Style (16th Edition):
Brown, Caitlin Westberg. “Notch3 promotes anoikis resistance via expression of col4α2
in epithelial ovarian cancer.” 2014. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:386266/.
MLA Handbook (7th Edition):
Brown, Caitlin Westberg. “Notch3 promotes anoikis resistance via expression of col4α2
in epithelial ovarian cancer.” 2014. Web. 17 Jan 2021.
Vancouver:
Brown CW. Notch3 promotes anoikis resistance via expression of col4α2
in epithelial ovarian cancer. [Internet] [Doctoral dissertation]. Brown University; 2014. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:386266/.
Council of Science Editors:
Brown CW. Notch3 promotes anoikis resistance via expression of col4α2
in epithelial ovarian cancer. [Doctoral Dissertation]. Brown University; 2014. Available from: https://repository.library.brown.edu/studio/item/bdr:386266/
16.
Hutchins, Noelle A.
The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal
Endothelial Cell Dysfunction in Sepsis.
Degree: PhD, Pathobiology, 2013, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:320516/
► This dissertation focuses on the response of liver sinusoidal endothelial cells (LSECs) to experimental sepsis in order to better understand the pathologic processes contributing to…
(more)
▼ This dissertation focuses on the response of liver
sinusoidal endothelial cells (LSECs) to experimental sepsis in
order to better understand the pathologic processes contributing to
acute liver injury (ALI) and ultimately multiple organ dysfunction
syndrome (MODS).
Under homeostatic conditions, the liver doesn’t respond to
microbial antigens that travel through the portal vein from the
digestive tract. In this regard, LSECs, represent a unique EC
population, believed to play a role in maintaining local immune
tolerance, in part, through the expression of two tolerogenic
molecules, Fas and programmed death ligand-1 (PD-L1). Although
these two cell surface molecules initiate independent signaling
cascades, their impact on LSEC function during sepsis is unknown.
Thus, the central hypothesis of this work was that increased Fas
expression on LSECs contributes to sepsis-induced liver injury,
while elevated PD-L1 expression on LSECs attempts to sustain the
immune tolerant state in the septic liver.
This dissertation explores how these two cell surface
molecules play a role on LSEC dysfunction in an animal sepsis model
(cecal ligation and puncture [CLP]). Sepsis fosters an infiltration
of leukocytes, which activate the sinusoidal endothelium, leading
to an increase of adhesion molecule expression. Subsequently, we
show that LSECs are susceptible to increased vascular permeability
and undergo Fas-mediated apoptosis during sepsis by comparing CLP
WT and CLP Fas-/- mice. Surprisingly, kupffer cells (KCs) appear to
protect LSECs from further sepsis-induced injury by secreting IL-6,
and engaging the endothelial IL-6 receptor.
In contrast to our hypothesis, increased PD-L1 does not
protect LSECs from sepsis-induced injury. PD-L1 gene deficiency in
CLP animals actually proves to be beneficial to LSEC survival and
permeability, essential aspects of EC function. PD-L1 gene
deficiency also decreases STAT3 activation, which has been shown to
protect ECs from endotoxin-injury. Unlike the suppression of Fas,
which drives LSEC injury, KCs may mediate this PD-L1 driven effect.
Overall, the results presented herein suggest that Fas and PD-L1
play important and unanticipated roles in LSEC dysfunction, which
develops in response to sepsis, contributing to hepatic injury
and/or organ dysfunction.
Advisors/Committee Members: Ayala, Alfred (Director), Reichner, Jonathan (Reader), Sharma, Surendra (Reader), Shaw, Sunil (Reader), Stearns-Kurosawa, Deborah (Reader).
Subjects/Keywords: sepsis
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hutchins, N. A. (2013). The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal
Endothelial Cell Dysfunction in Sepsis. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:320516/
Chicago Manual of Style (16th Edition):
Hutchins, Noelle A. “The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal
Endothelial Cell Dysfunction in Sepsis.” 2013. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:320516/.
MLA Handbook (7th Edition):
Hutchins, Noelle A. “The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal
Endothelial Cell Dysfunction in Sepsis.” 2013. Web. 17 Jan 2021.
Vancouver:
Hutchins NA. The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal
Endothelial Cell Dysfunction in Sepsis. [Internet] [Doctoral dissertation]. Brown University; 2013. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:320516/.
Council of Science Editors:
Hutchins NA. The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal
Endothelial Cell Dysfunction in Sepsis. [Doctoral Dissertation]. Brown University; 2013. Available from: https://repository.library.brown.edu/studio/item/bdr:320516/
17.
Stout, David Andrew.
Analysis of nanostructuredve vs Lipopolysaccharide (LPS)
Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using
Traction Force Microscopy.
Degree: PhD, Biomedical Engineering, 2014, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:386196/
► Understanding the fundamental mechanisms, and forces, underlying cell migration holds the promise of effective approaches for treating diseases and promoting cellular transplantation. One such disease…
(more)
▼ Understanding the fundamental mechanisms, and forces,
underlying cell migration holds the promise of effective approaches
for treating diseases and promoting cellular transplantation. One
such disease is sepsis. During sepsis – a complex clinical syndrome
that results from a harmful or damaging host response to
infection – directed impairment has been shown of neutrophils to
infectious foci and inadequate antimicrobial responses. In order to
understand how sepsis affects neutrophil migration, we investigated
the force generating characteristics and comparison between normal
and septic neutrophil chemotaxis in a physiological relevant 3D
mechanistically tractable system with the use of 3D FIDVC
techniques. The development of a well controlled diffusion
direct-viewing system was completed for chemotaxis studies, which
allows one to overcome modern chemotaxis chamber obstacles. More
compelling, we were able to successfully calculate the coefficient
of diffusion of Rhodamine through five different concentrations of
collagen as well as solve the governing diffusion equations to find
the specific concentration along the surface of the cell. With the
use of time-lapsed confocal microscopy and FIDVC we were able to
probe the force generating chemotactic characteristic differences
of naive and LPS activated neutrophils. We were able to show that
in 3D, LPS activated neutrophils have greater deformation and
displacement capabilities, while increasing their speed and
decreasing their directness. Investigating the signaling pathways
between fMLP and LPS our research suggests a molecule used in both
GPCR and TRL4 pathways is being affected which may shed light in
understanding sepsis. By introducing the study of mechanics in the
investigation of sepsis, we have presented insight (force
generation location and mobility) on how sepsis may alter
neutrophil function that may not have been noticed by traditional
biological assays.
Advisors/Committee Members: Franck, Christian (Director), Reichner, Jonathan (Reader), Tripathi, Anubhav (Reader), Darling, Eric (Reader), Hammer, Daniel (Reader).
Subjects/Keywords: Traction Force Microscopy
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Stout, D. A. (2014). Analysis of nanostructuredve vs Lipopolysaccharide (LPS)
Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using
Traction Force Microscopy. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:386196/
Chicago Manual of Style (16th Edition):
Stout, David Andrew. “Analysis of nanostructuredve vs Lipopolysaccharide (LPS)
Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using
Traction Force Microscopy.” 2014. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:386196/.
MLA Handbook (7th Edition):
Stout, David Andrew. “Analysis of nanostructuredve vs Lipopolysaccharide (LPS)
Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using
Traction Force Microscopy.” 2014. Web. 17 Jan 2021.
Vancouver:
Stout DA. Analysis of nanostructuredve vs Lipopolysaccharide (LPS)
Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using
Traction Force Microscopy. [Internet] [Doctoral dissertation]. Brown University; 2014. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:386196/.
Council of Science Editors:
Stout DA. Analysis of nanostructuredve vs Lipopolysaccharide (LPS)
Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using
Traction Force Microscopy. [Doctoral Dissertation]. Brown University; 2014. Available from: https://repository.library.brown.edu/studio/item/bdr:386196/
18.
Byrd, Angel Shree'.
Abstract of, “Regulation of Human Neutrophil Functions by
the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of
Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd,
Ph.D., Brown University, May 2014.
Degree: PhD, Pathobiology, 2014, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:386316/
► Neutrophil-mediated host defense against pathogens includes the extrusion of a lattice of DNA and microbicidal enzymes known as Neutrophil Extracellular Traps (NETs). The receptor:ligand interactions…
(more)
▼ Neutrophil-mediated host defense against pathogens
includes the extrusion of a lattice of DNA and microbicidal enzymes
known as Neutrophil Extracellular Traps (NETs). The receptor:ligand
interactions and intracellular signaling mechanisms responsible for
elaborating NETs were determined for the response to Candida
albicans. Since the host response of extravasated neutrophils to
mycotic infections within tissues necessitates contact with ECM,
this study also identified a novel and significant regulatory role
for the ubiquitous matrix component fibronectin (Fn) in NET
release. We report that recognition of purified fungal
pathogen-associated molecular pattern β-glucan by human neutrophils
causes rapid (≤ 30 mins) homotypic aggregation and NET release by a
mechanism that requires Fn. Alone, immobilized β-glucan induces
reactive oxygen species (ROS) production but not NET release,
whereas in the context of Fn, ROS production is suppressed and NETs
are extruded. NET release to Fn + β-glucan is robust, accounting
for 17.2 ± 3.4% of total DNA in the cell population. Release is
dependent on β-glucan recognition by CR3 (CD11b/CD18), but not
Dectin-1, or ROS. The process of NET release included filling of
intracellular vesicles with nuclear material that was eventually
extruded. We identify a role for ERK in homotypic aggregation and
NET release. NET formation to C. albicans hyphae was also found to
depend on β-glucan recognition by CR3, require Fn and ERK but not
ROS, and results in hyphal destruction. We report a new regulatory
mechanism of NETosis in which the extracellular matrix is a key
component of the rapid anti-fungal response. We also report that
neonatal neutrophils formed aggregates and released NETs rapidly
and independent of ROS production. Providing additional evidence of
the ROS independent mechanism of aggregation and NET release,
neutrophils from Chronic Granulomatous Disease (CGD) patients
formed large homotypic aggregates and released NETs to β-glucan and
Fn. Therefore, the susceptibility of these immunocompromised
populations to fungal infections may not be due to an inherent
inability of neutrophils to aggregate and produce NETs in response
to the fungal PAMP β-glucan. Ultimately, we hope innovative
therapeutic approaches can mediate a regulatory balance in
immunocompromised patients to improve health
outcomes.
Advisors/Committee Members: Reichner, Jonathan (Director), Gruppuso, Philip (Reader), Sanders, Jennifer (Reader), Frackelton, A. Raymond (Reader), Salomon, Arthur (Reader).
Subjects/Keywords: NEONATES
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Byrd, A. S. (2014). Abstract of, “Regulation of Human Neutrophil Functions by
the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of
Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd,
Ph.D., Brown University, May 2014. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:386316/
Chicago Manual of Style (16th Edition):
Byrd, Angel Shree'. “Abstract of, “Regulation of Human Neutrophil Functions by
the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of
Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd,
Ph.D., Brown University, May 2014.” 2014. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:386316/.
MLA Handbook (7th Edition):
Byrd, Angel Shree'. “Abstract of, “Regulation of Human Neutrophil Functions by
the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of
Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd,
Ph.D., Brown University, May 2014.” 2014. Web. 17 Jan 2021.
Vancouver:
Byrd AS. Abstract of, “Regulation of Human Neutrophil Functions by
the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of
Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd,
Ph.D., Brown University, May 2014. [Internet] [Doctoral dissertation]. Brown University; 2014. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:386316/.
Council of Science Editors:
Byrd AS. Abstract of, “Regulation of Human Neutrophil Functions by
the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of
Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd,
Ph.D., Brown University, May 2014. [Doctoral Dissertation]. Brown University; 2014. Available from: https://repository.library.brown.edu/studio/item/bdr:386316/
19.
Toussaint, Leon E.
Invariant Natural Killer T Cell Development is Uniquely
Regulated by Y-Chromosome Genes and SHIP-1.
Degree: PhD, Pathobiology, 2012, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:297571/
► The Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP-1) plays a critical role in regulating the phosphoinositide 3-kinases (PI3Ks) signaling pathway. PI3Ks are important for…
(more)
▼ The Src homology 2 (SH2) domain-containing
inositol-5-phosphatase 1 (SHIP-1) plays a critical role in
regulating the phosphoinositide 3-kinases (PI3Ks) signaling
pathway. PI3Ks are important for the development, differentiation
and function of lymphocyte and myeloid cells, and SHIP-1 has been
implicated in the function, development and maintenance of these
cells. However a clear impact of SHIP-1 on the invariant natural
killer T (iNKT) cell population has yet to be investigated. iNKT
cells are a unique subset of T lymphocytes which share some
characteristics with mainstream T cells, but have distinct
functions and a separate development program. Due to this
divergence from the conventional T cell developmental program, many
factors specific to iNKT cell development and function have been
discovered. Our current studies delve further into factors that
influence the iNKT cell population. In chapter 2, by Investigation
of a unique Y-chromosome mutation we explore the development iNKT
cells in relation to Y-linked genes. The use of targeted breeding
strategies and microarray analysis allowed for the discovery of
four Y-linked genes that may possibly play an essential role in
iNKT cells development. In chapter 3 of this dissertation we also
look at the influence of SHIP-1 on the iNKT cell population in mice
and by extensive examinations of the T lymphocyte compartments we
reveal an undiscovered global T lymphocyte requirement of SHIP-1.
Although many past studies have revealed factors such as signal
transduction and transcription factors, cytokines and surface
molecules that influence iNKT cell development and function there
has never been a study which explored the impact of Y-linked genes
or SHIP-1 on iNKT cells.
Advisors/Committee Members: Brossay, Laurent (Director), Reichner, Jonathan (Reader), Gregory, Stephen (Reader), Bungiro, Richard (Reader), Boyaka, Prosper (Reader).
Subjects/Keywords: Y-linked genes
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Toussaint, L. E. (2012). Invariant Natural Killer T Cell Development is Uniquely
Regulated by Y-Chromosome Genes and SHIP-1. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297571/
Chicago Manual of Style (16th Edition):
Toussaint, Leon E. “Invariant Natural Killer T Cell Development is Uniquely
Regulated by Y-Chromosome Genes and SHIP-1.” 2012. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:297571/.
MLA Handbook (7th Edition):
Toussaint, Leon E. “Invariant Natural Killer T Cell Development is Uniquely
Regulated by Y-Chromosome Genes and SHIP-1.” 2012. Web. 17 Jan 2021.
Vancouver:
Toussaint LE. Invariant Natural Killer T Cell Development is Uniquely
Regulated by Y-Chromosome Genes and SHIP-1. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:297571/.
Council of Science Editors:
Toussaint LE. Invariant Natural Killer T Cell Development is Uniquely
Regulated by Y-Chromosome Genes and SHIP-1. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297571/
20.
Andrews, Christina.
A Biophysical Analysis of Neutrophil Force Generation in a
Biochemical Environment.
Degree: Biomedical Engineering, 2018, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:792823/
► Neutrophils are the most abundant circulating white blood cell in the human body, and play a crucial role in the innate immune response to infection…
(more)
▼ Neutrophils are the most abundant circulating white
blood cell in the human body, and play a crucial role in the innate
immune response to infection and inflammation. Sepsis is a systemic
bacterial infection that results in a complex immune response. In
this event, neutrophils are exposed to an excess of chemical
stimuli that results in over activation. These over-activated
neutrophils cause tissue damage, organ dysfunction, and death. In
this project, I will study the change in cellular mechanisms
between naïve and lipopolysaccharide (LPS)-activated neutrophils by
quantifying the material displacement fields and surface tractions.
This will provide information moving forward to understand the
mechanical dysregulation that neutrophils undergo at a heightened
activation state. This data will aid our understanding of
neutrophil biochemical and mechanical sensing to recognize injury,
and then migrate to the site of injury. In this study, I will
identify the change in neutrophil motility and force generation
before and after LPS activation. I use human fibronectin and human
ICAM-1 coated on mechanically tunable polyacrylamide hydrogels
(E=1.7 kPa and 8.7 kPa) to study naïve and LPS-activated
neutrophils. By studying material displacement fields and surface
tractions, the Franck Lab will better understand healthy and
over-activated neutrophil motility and identify key phenotypic
markers to detect and provide treatment in the event of sepsis.
This will further help establish a baseline on the relationship
between mechanics and cellular mechanisms, with a focus on
neutrophil migration and adhesion.
Advisors/Committee Members: Franck, Christian (Advisor), Lefort, Craig (Reader), Reichner, Jonathan (Reader), Wong, Ian (Reader).
Subjects/Keywords: Immunology
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Andrews, C. (2018). A Biophysical Analysis of Neutrophil Force Generation in a
Biochemical Environment. (Thesis). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:792823/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Andrews, Christina. “A Biophysical Analysis of Neutrophil Force Generation in a
Biochemical Environment.” 2018. Thesis, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:792823/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Andrews, Christina. “A Biophysical Analysis of Neutrophil Force Generation in a
Biochemical Environment.” 2018. Web. 17 Jan 2021.
Vancouver:
Andrews C. A Biophysical Analysis of Neutrophil Force Generation in a
Biochemical Environment. [Internet] [Thesis]. Brown University; 2018. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:792823/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Andrews C. A Biophysical Analysis of Neutrophil Force Generation in a
Biochemical Environment. [Thesis]. Brown University; 2018. Available from: https://repository.library.brown.edu/studio/item/bdr:792823/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
21.
O'Brien, Xian Marie.
Innate Immune Functions of Human Polymorphonuclear
Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1
Integrin Engagement and β-glucan, a Fungal Pathogen Associated
Molecular Pattern.
Degree: PhD, Pathobiology, 2010, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:11088/
► Invasive fungal infections are emerging as a significant cause of morbidity and mortality, especially among the increasing immunosuppressed patient populations. Transition to a filamentous hyphal…
(more)
▼ Invasive fungal infections are emerging as a
significant cause of morbidity and mortality, especially among the
increasing immunosuppressed patient populations. Transition to a
filamentous hyphal morphology, which is not easily cleared by
phagocytosis, correlates strongly with invasiveness and virulence.
This dissertation explored the effects of β-glucan, a component of
the pathogenic yeast cell wall, on human polymorphonuclear
leukocyte (PMN) respiratory burst, migration and mechanosensing as
mediated through the β2 integrin, CR3 (αMβ2). CR3 is a known
β-glucan receptor via a lectin-like domain. These and other studies
from our laboratory have shown that β-glucan accelerates chemotaxis
of PMNs when added to a fibronectin (Fn) matrix. We show that
immobilized β-glucan stimulates plasma membrane-associated
respiratory burst, which is inhibited by Fn. β-glucan was shown to
exhort its PMN priming effects through CR3 modulated in part
through a system of β1-to-β2 integrin cross talk with VLA3 (α3β1)
and VLA5 (α5β1). A putative mechanism through p38 MAPK and Lyn PTK
is proposed. We show that PMN migration on the CR3 ligand
fibrinogen is independent of substrate stiffness, unlike the
β1-mediated migration of PMNs on Fn. Migration in the presence of
soluble β-glucan significantly increased PMN polarity index and
significantly reduced the percentage of PMNs that initiated a
respiratory burst before reaching the chemoattractant source. Taken
together, these data suggest that activation of β1 integrins and
priming by β-glucan elaborated by a fungal infection may determine
an inflammatory cell phenotype that is well suited to eliminate the
virulent, filamentous form of fungi by accelerating chemotaxis
towards the foci of infection while suppressing the premature
release of oxidants until the neutrophil establishes direct
multifocal contact with hyphae. Additionally, fluorescence
resonance energy transfer (FRET) based reporter constructs for CR3
activation and avidity were generated that provide evidence for
conformational changes in the cytoplasmic domains of CR3 during
physiologic activation, as well priming with soluble β-glucan. We
also extended this by developing a differentiated HL-60 system that
allows for the tracking of CR3 dynamic regulation during relevant
PMN cellular functions.
Advisors/Committee Members: Reichner, Jonathan (Director), Atwood, Walter (Reader), Wessel, Gary (Reader), Jay, Tang (Reader), Jun, Yan (Reader).
Subjects/Keywords: respiratory burst
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
O'Brien, X. M. (2010). Innate Immune Functions of Human Polymorphonuclear
Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1
Integrin Engagement and β-glucan, a Fungal Pathogen Associated
Molecular Pattern. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:11088/
Chicago Manual of Style (16th Edition):
O'Brien, Xian Marie. “Innate Immune Functions of Human Polymorphonuclear
Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1
Integrin Engagement and β-glucan, a Fungal Pathogen Associated
Molecular Pattern.” 2010. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:11088/.
MLA Handbook (7th Edition):
O'Brien, Xian Marie. “Innate Immune Functions of Human Polymorphonuclear
Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1
Integrin Engagement and β-glucan, a Fungal Pathogen Associated
Molecular Pattern.” 2010. Web. 17 Jan 2021.
Vancouver:
O'Brien XM. Innate Immune Functions of Human Polymorphonuclear
Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1
Integrin Engagement and β-glucan, a Fungal Pathogen Associated
Molecular Pattern. [Internet] [Doctoral dissertation]. Brown University; 2010. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:11088/.
Council of Science Editors:
O'Brien XM. Innate Immune Functions of Human Polymorphonuclear
Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1
Integrin Engagement and β-glucan, a Fungal Pathogen Associated
Molecular Pattern. [Doctoral Dissertation]. Brown University; 2010. Available from: https://repository.library.brown.edu/studio/item/bdr:11088/
22.
Toorie, Anika M.
The role of hypothalamic Sirt1 in the regulation of the
hypophysiotropic adrenal and thyroid axes.
Degree: PhD, Pathobiology, 2015, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:419479/
► Sirtuin 1 is a metabolic sensor that has a role in metabolic homeostasis in the periphery and at the central level. Its role in the…
(more)
▼ Sirtuin 1 is a metabolic sensor that has a role in
metabolic homeostasis in the periphery and at the central level.
Its role in the periphery has been heavily studied and studies
demonstrate peripheral Sirt1 in protecting against the development
of obesity and mitigating adverse phenotypes that are associated
with obesity, such as insulin resistance. Brain Sirt1’s role in
energy balance is less established as studies have provided
conflicting evidence regarding its role in energy homeostasis.
Others and we demonstrated a role of Sirt1 in promoting a positive
energy balance by affecting both food intake and energy
expenditure. Findings from Dr. Nillni’s laboratory were amongst the
first to reveal that Sirt1 functions in an orexigenic capacity, an
effect that was mediated via the transcription factor FoxO1, and
its actions on the central melanocortin system. The work described
in this dissertation extends upon those earlier findings and
elucidates the role of hypothalamus Sirt1 in the diet induced obese
(DIO) condition. We demonstrate a novel regulation of the HPA axis
by Sirt1 expressed in the hypothalamus paraventricular nucleus
(PVN). The results reveal that Sirt1 is increased in the PVN of DIO
rats and that this is associated with elevated basal
corticosterone, which is known to promote a positive energy balance
by instigating food intake. Inhibiting PVN Sirt1 activity resulted
in a decrease in PVN prohormone convertase 2, which is one of the
processing enzymes responsible for the processing of
proCorticotropin releasing hormone into the bioactive CRH molecule,
as well as the amount of CRH targeted to the median eminence. These
effects were associated with reduced basal corticosterone;
alongside an increase in insulin that we posit may precede enhanced
insulin sensitivity. We also show that Sirt1 is increased in the
hypothalamus arcuate nucleus of DIO rats and that central
inhibition of Sirt1 activity is sufficient to reduce body weight
gain in DIO rats due to an increase in HPT activity and energy
expenditure. The findings presented here reveal a role of ARC and
PVN Sirt1 in promoting metabolic dysfunction and suggests
hypothalamic Sirt1 inhibition as an effective target against
obesity.
Advisors/Committee Members: Nillni, Eduardo (Director), Reichner, Jonathan (Reader), Oancea, Elena (Reader), Marshall, John (Reader), Wardlaw, Sharon (Reader), Nillni, Eduardo (Director), Reichner, Jonathan (Reader), Oancea, Elena (Reader), Marshall, John (Reader), Wardlaw, Sharon (Reader).
Subjects/Keywords: diet induced obesity
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Toorie, A. M. (2015). The role of hypothalamic Sirt1 in the regulation of the
hypophysiotropic adrenal and thyroid axes. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:419479/
Chicago Manual of Style (16th Edition):
Toorie, Anika M. “The role of hypothalamic Sirt1 in the regulation of the
hypophysiotropic adrenal and thyroid axes.” 2015. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:419479/.
MLA Handbook (7th Edition):
Toorie, Anika M. “The role of hypothalamic Sirt1 in the regulation of the
hypophysiotropic adrenal and thyroid axes.” 2015. Web. 17 Jan 2021.
Vancouver:
Toorie AM. The role of hypothalamic Sirt1 in the regulation of the
hypophysiotropic adrenal and thyroid axes. [Internet] [Doctoral dissertation]. Brown University; 2015. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:419479/.
Council of Science Editors:
Toorie AM. The role of hypothalamic Sirt1 in the regulation of the
hypophysiotropic adrenal and thyroid axes. [Doctoral Dissertation]. Brown University; 2015. Available from: https://repository.library.brown.edu/studio/item/bdr:419479/
23.
Johnson, Courtney Michele.
Molecular Mechanisms Underlying The Human Neutrophil
Response To Fungal Beta-Glucan In The Context Of The Extracellular
Matrix Protein Fibronectin.
Degree: PhD, Pathobiology, 2015, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:419450/
► Complement Receptor 3 (CR3), a β2 integrin found on neutrophils, plays an important role in fungal recognition and immune response. Co-ligation of CR3 with fibronectin…
(more)
▼ Complement Receptor 3 (CR3), a β2 integrin found on
neutrophils, plays an important role in fungal recognition and
immune response. Co-ligation of CR3 with fibronectin (Fn), an
ubiquitous extracellular matrix component, at the I-domain and
β-glucan (B), a glucose polymer found in fungal cell walls, at the
lectin-like domain is possible due to spatially distinct locations.
Dual ligation of CR3 with Fn+B induces homotypic aggregation of
primed neutrophils, a response representative of the immune cells
encounter with fungi within tissues and that can be blocked by
anti-CR3 antibody. Previous findings have shown that CR3-mediated
DNA Neutrophillic Extracellular Traps (NETS) coincide with PMN
aggregates. To understand the molecular mechanisms of how CR3
coordinates these neutrophil responses, this thesis explores the
role of the integrins CR3 as well as the β1 integrin family members
VLA3 and VLA5. Using antibody blockade and receptor-FRET, we
unexpectedly discovered a CR3-mediated required role for VLA3, the
canonical laminin receptor, in aggregate formation. The role of
VLA3 in aggregate formation was specific as blockade of other β1
integrin family members such as VLA5, the canonical Fn receptor,
failed to prevent aggregation. Exploring the role of VLA5, we were
able to show a decrease in overall VLA5 activity on Fn+B and by
using an activating anti-VLA5 antibody, that active inhibition of
VLA5 activity is necessary for aggregate formation. In assessing
NETs formation, we discovered that unlike aggregate formation, VLA5
and CR3 are necessary for NET formation, where VLA3 is not.
Furthermore, activation of VLA5 with the activating VLA5 antibody
does not inhibit NET formation. Finally, a correlative signaling
role for p-ERK and p-GSK-3β was determined in the neutrophil
responses to β-glucan and Fn but not to either alone. Within this
thesis, a novel, complex and temporally regulated cross-talk
pathway was uncovered in which dual ligation of CR3 signals the
differential regulation of individual β1 integrins not often
associated with anti-fungal activity. Furthermore, it was
discovered that NETosis and aggregation are controlled by the
activation state of distinct β1 integrins, VLA5 and VLA3,
respectively.
Advisors/Committee Members: Reichner, Jonathan (Director), Bowen, Wayne (Reader), Bliss, Joseph (Reader), Sanders, Jennifer (Reader), Luscinskas, Francis (Reader), Fast, Loren (Director).
Subjects/Keywords: Complement Receptor 3
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Johnson, C. M. (2015). Molecular Mechanisms Underlying The Human Neutrophil
Response To Fungal Beta-Glucan In The Context Of The Extracellular
Matrix Protein Fibronectin. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:419450/
Chicago Manual of Style (16th Edition):
Johnson, Courtney Michele. “Molecular Mechanisms Underlying The Human Neutrophil
Response To Fungal Beta-Glucan In The Context Of The Extracellular
Matrix Protein Fibronectin.” 2015. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:419450/.
MLA Handbook (7th Edition):
Johnson, Courtney Michele. “Molecular Mechanisms Underlying The Human Neutrophil
Response To Fungal Beta-Glucan In The Context Of The Extracellular
Matrix Protein Fibronectin.” 2015. Web. 17 Jan 2021.
Vancouver:
Johnson CM. Molecular Mechanisms Underlying The Human Neutrophil
Response To Fungal Beta-Glucan In The Context Of The Extracellular
Matrix Protein Fibronectin. [Internet] [Doctoral dissertation]. Brown University; 2015. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:419450/.
Council of Science Editors:
Johnson CM. Molecular Mechanisms Underlying The Human Neutrophil
Response To Fungal Beta-Glucan In The Context Of The Extracellular
Matrix Protein Fibronectin. [Doctoral Dissertation]. Brown University; 2015. Available from: https://repository.library.brown.edu/studio/item/bdr:419450/
24.
Crane, Meredith J.
Innate Immune Events Promoting Antiviral Defense during MCMV
Infection.
Degree: PhD, Pathobiology, 2012, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:297563/
► The studies presented in this thesis investigated innate immune events in the liver during acute infection with murine cytomegalovirus (MCMV). While many responses that occur…
(more)
▼ The studies presented in this thesis investigated
innate immune events in the liver during acute infection with
murine cytomegalovirus (MCMV). While many responses that occur in
the liver are well understood, the mechanism of viral sensing is
not known. The first set of studies investigated whether nucleic
acid-sensing TLRs mediate MCMV recognition and promote liver
antiviral responses. Mice that cannot signal through these TLRs due
to a point mutation in UNC93B1 were infected to assess downstream
immune responses. Infected UNC93B1-deficient mice were severely
impaired in proinflammatory cytokine production, with delayed
accumulation of plasmacytoid dendritic cells and natural killer
cells in the liver, although T cell responses were intact.
Additionally, these mice had more severe liver pathology and
increased serum ALT levels. Ultimately, UNC93B1-deficient mice were
significantly impaired in their ability to clear the virus from the
liver. Thus, signaling through nucleic acid-sensing TLRs is
necessary for MCMV recognition and downstream responses in the
liver. In addition to MCMV recognition, early infiltration of
monocytes to the liver is critical in promoting antiviral defense
during acute infection. A second set of studies investigated the
role of the chemokine receptor CCR2 in recruiting inflammatory
monocytes from the bone marrow to peripheral sites, such as the
liver, during MCMV infection. It was hypothesized that CCR2
activation is required for inflammatory monocyte mobilization from
the bone marrow. In MCMV-infected CCR2-deficent mice, inflammatory
monocytes accumulated in the bone marrow and were absent in the
circulation. In wild type mice, it was also found that F4/80+ cells
in the bone marrow produce CCR2 ligands in an IFN-α-dependent
manner concurrent with monocyte egress. These results suggest that
early MCMV recognition induces IFN-α, which signals CCR2 ligand
production in the bone marrow to promote the egress of
CCR2-expressing inflammatory monocytes to peripheral sites of
infection. Together, these studies contribute to our understanding
of the early immune events that promote liver antiviral defense
during acute MCMV infection.
Advisors/Committee Members: Salazar-Mather, Thais (Director), Reichner, Jonathan (Reader), Brossay, Laurent (Reader), Atwood, Walter (Reader), Kurt-Jones, Evelyn (Reader).
Subjects/Keywords: MCMV
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Crane, M. J. (2012). Innate Immune Events Promoting Antiviral Defense during MCMV
Infection. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297563/
Chicago Manual of Style (16th Edition):
Crane, Meredith J. “Innate Immune Events Promoting Antiviral Defense during MCMV
Infection.” 2012. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:297563/.
MLA Handbook (7th Edition):
Crane, Meredith J. “Innate Immune Events Promoting Antiviral Defense during MCMV
Infection.” 2012. Web. 17 Jan 2021.
Vancouver:
Crane MJ. Innate Immune Events Promoting Antiviral Defense during MCMV
Infection. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:297563/.
Council of Science Editors:
Crane MJ. Innate Immune Events Promoting Antiviral Defense during MCMV
Infection. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297563/
25.
Ramirez, Teresa.
Contributions of Insulin Resistance, Endoplasmic Reticulum
Stress, and Ceramides in Alcoholic Liver Disease.
Degree: PhD, Molecular Pharmacology, Physiology, and
Biotechnology, 2014, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:386183/
► Background: Chronic alcoholic liver disease is associated with hepatic insulin resistance, inflammation, oxidative and ER stress, mitochondrial dysfunction, and DNA damage. Peroxisome proliferator activated receptor…
(more)
▼ Background: Chronic alcoholic liver disease is
associated with hepatic insulin resistance, inflammation, oxidative
and ER stress, mitochondrial dysfunction, and DNA damage.
Peroxisome proliferator activated receptor (PPAR) agonists are
insulin sensitizers that have anti-inflammatory/anti-oxidant
effects. Hypothesis: We hypothesized that treatment with insulin
sensitizer agents, can restore hepatic insulin signaling in ethanol
exposed livers and will reduce ceramide accumulation and ER stress.
Herein, we furthered our investigations by characterizing the
histological and ultrastructural changes mediated by PPAR agonist
rescue of alcohol-induced steatohepatitis. Methods: Adult male Long
Evans rats were pair fed with isocaloric liquid diets containing 0%
or 37% ethanol (caloric) for 8 weeks. After 3 weeks on the diets,
rats were treated with vehicle, or a PPAR-alpha, PPAR-delta, or
PPAR-gamma agonist twice weekly by i.p. injection. Results:
Ethanol-fed rats developed steatohepatitis with disordered hepatic
chord architecture, mega-mitochondria, disruption of the RER,
increased apoptosis, and increased 4-hydroxynonenal (HNE) and
3-nitrotyrosine (NTyr) immunoreactivity. PPAR-delta and PPAR-gamma
agonists reduced the severity of steatohepatitis, and restored the
hepatic chord-like architecture, mitochondrial morphology, and RER
organization, and the PPAR-delta agonist significantly reduced
hepatic HNE. On the other hand, prominent RER tubule dilation,
which could reflect ER stress, persisted in ethanol-exposed,
PPAR-gamma treated, but not PPAR-delta treated livers. The
PPAR-alpha agonist exacerbated both steatohepatitis and formation
of mega-mitochondria, and it failed to restore RER architecture or
lower biochemical indices of oxidative stress. Conclusion: Improved
hepatic insulin responsiveness and decreased inflammation resulting
from PPAR-delta or PPAR-gamma agonist treatments of alcohol-induced
steatohepatitis are likely mediated by enhanced signaling through
metabolic pathways with attendant reductions in ER stress,
oxidative stress, and mitochondrial dysfunction.
Advisors/Committee Members: de la Monte, Suzanne (Director), Wands, Jack (Reader), Hai, Chi-Ming (Reader), Reichner, Jonathan (Reader), Wan, Yinsheng (Reader).
Subjects/Keywords: Alcoholic liver disease; Experimental model; PPAR
agonists; Steato-hepatitis; Insulin Resistance; Histopathology;
Electron microscopy; ER stress
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ramirez, T. (2014). Contributions of Insulin Resistance, Endoplasmic Reticulum
Stress, and Ceramides in Alcoholic Liver Disease. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:386183/
Chicago Manual of Style (16th Edition):
Ramirez, Teresa. “Contributions of Insulin Resistance, Endoplasmic Reticulum
Stress, and Ceramides in Alcoholic Liver Disease.” 2014. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:386183/.
MLA Handbook (7th Edition):
Ramirez, Teresa. “Contributions of Insulin Resistance, Endoplasmic Reticulum
Stress, and Ceramides in Alcoholic Liver Disease.” 2014. Web. 17 Jan 2021.
Vancouver:
Ramirez T. Contributions of Insulin Resistance, Endoplasmic Reticulum
Stress, and Ceramides in Alcoholic Liver Disease. [Internet] [Doctoral dissertation]. Brown University; 2014. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:386183/.
Council of Science Editors:
Ramirez T. Contributions of Insulin Resistance, Endoplasmic Reticulum
Stress, and Ceramides in Alcoholic Liver Disease. [Doctoral Dissertation]. Brown University; 2014. Available from: https://repository.library.brown.edu/studio/item/bdr:386183/
26.
Longato, Lisa.
Pathogenic mechanisms and consequences of
steatohepatitis.
Degree: PhD, Pathobiology, 2012, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:297566/
► The mechanisms by which steatohepatitis in alcoholic (ALD) or non-alcoholic (NAFLD) fatty liver disease becomes progressive and advances to stages of fibrosis, cirrhosis, and liver…
(more)
▼ The mechanisms by which steatohepatitis in alcoholic
(ALD) or non-alcoholic (NAFLD) fatty liver disease becomes
progressive and advances to stages of fibrosis, cirrhosis, and
liver failure are poorly understood. We hypothesize that shifts in
hepatic lipid composition that favor the accumulation of bioactive,
toxic lipids promote insulin resistance, which leads to increased
mitochondrial dysfunction, oxidative stress, inflammation, cell
injury and death. The overarching goal of this research was to
examine the roles of aberrant ceramide generation and accumulation
in the pathogenesis of progressive steatohepatitis in ALD and NAFLD
in both humans and experimental models. Using molecular and
biochemical approaches, we found that both chronic high fat and
alcohol feeding significantly up-regulated pro-ceramide gene
expression and enzymatic activity via several pathways.
Furthermore, these effects were associated with increased hepatic
insulin resistance. Parallel studies in livers from patients with
advanced ALD highlighted similar, but more severe changes involving
pro-ceramide metabolism as well as insulin resistance, indicating
the relevance of these findings with respect to the human disease.
In vitro experiments using hepatocellular cell lines or
precision-cut liver slice cultures demonstrated that: 1) exogenous
exposure to short-chain ceramides impairs insulin signaling,
mitochondrial function, and energy metabolism; 2) treatment with
chemical inhibitors of pro-ceramide enzymes partially reverse the
hepatotoxic effects of steatohepatitis. Overall, these results
indicate that ceramide can serve as a lipid mediator of injury and
insulin resistance in both ALD and NAFLD-associated
steatohepatitis. Furthermore, the results suggest that, in both
conditions, therapeutic strategies for preventing disease
progression must be multi-pronged to support insulin responsiveness
and inhibit toxic lipid accumulation and attendant tissue damage
mediated by ER stress, mitochondrial dysfunction, and inflammation.
Advisors/Committee Members: De la Monte, Suzanne (Director), Gruppuso, Philip (Reader), Kurtis, Jonathan (Reader), Reichner, Jonathan (Reader), Akhlaghi, Fatemeh (Reader).
Subjects/Keywords: NAFLD
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Longato, L. (2012). Pathogenic mechanisms and consequences of
steatohepatitis. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297566/
Chicago Manual of Style (16th Edition):
Longato, Lisa. “Pathogenic mechanisms and consequences of
steatohepatitis.” 2012. Doctoral Dissertation, Brown University. Accessed January 17, 2021.
https://repository.library.brown.edu/studio/item/bdr:297566/.
MLA Handbook (7th Edition):
Longato, Lisa. “Pathogenic mechanisms and consequences of
steatohepatitis.” 2012. Web. 17 Jan 2021.
Vancouver:
Longato L. Pathogenic mechanisms and consequences of
steatohepatitis. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2021 Jan 17].
Available from: https://repository.library.brown.edu/studio/item/bdr:297566/.
Council of Science Editors:
Longato L. Pathogenic mechanisms and consequences of
steatohepatitis. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297566/
.