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You searched for +publisher:"University of Alabama – Birmingham" +contributor:("Kabarowski, Janusz H. S."). Showing records 1 – 3 of 3 total matches.

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1. Sweetwyne, Mariya T. Regulation of tissue remodeling through the calreticulin binding domain of thrombospondin-1.

Degree: PhD, 2009, University of Alabama – Birmingham

Thrombospondin-1 (TSP1) is a multifunctional matricellular protein released by platelets in response to injury and secreted by cells under stress. TSP1 is cleaved into functional N- and C-terminal domain fragments, which have paradoxical actions with respect to angiogenesis, cell survival, and cell adhesion. Wound healing studies by others demonstrated that TSP1 knockout mice have delayed rates of wound closure, which was attributed to actions of the C-terminal domain. We wished to investigate the specific role of the N-terminal domain in tissue remodeling. Previously, we established that a sequence (aa 17-35) in the N-terminal domain of TSP1 induces focal adhesion disassembly, stimulates cell migration, and prevents anoikis. These actions occur when TSP1 binds to cell surface calreticulin (CRT) associated with LDL receptor-related protein 1 (LRP1). To determine the role of TSP1 signaling through the CRT/LRP1 co-complex in tissue remodeling, we utilized a model of the foreign body response. Surgical sponges filled with collagen and a plasmid encoding the TSP1 signal peptide, followed by the CRT-binding sequence tagged with enhanced green fluorescent protein [NTD (1-35)-EGFP] were implanted subcutaneously in mice. Cells responding to the insult of implantation ingest the collagen-plasmid mixture, initiating localized transfection. A plasmid encoding two amino acid substitutions within the CRT-binding sequence was used as an inactive control [NTD mod (1-35)-EGFP]. EGFP expression in the sponge implants from the transfection of invading cells was confirmed over days 5-21. Unexpectedly, mice with induced expression of NTD (1-35)-EFGP showed an accelerated and highly organized collagen encapsulation of the implant. Therefore, human dermal fibroblasts were treated with the TSP1, a recombinant NTD, or the TSP1-CRT binding sequence to determine whether TSP1 directly regulates collagen. TSP1 and the TSP1-CRT binding sequence stimulated increased expression of fibrillar collagens, collagen deposition into the ECM, and levels of collagen I and III mRNA. TSP1 stimulation of collagen was blocked by a peptide (CRT19-36) that inhibits TSP binding to CRT. Furthermore, the increase in collagen signaled by the TSP1-CRT binding sequence was independent of TGFβ-1 activation and Smad-2 phosphorylation. These results demonstrate a novel role for the N-terminal domain of TSP1 in tissue remodeling and collagen regulation.

1 online resource (xi, 135 p. : ill., digital, PDF file)

Cell Biology

Joint Health Sciences

Thrombospondin-1 Calreticulin Matricellular Foreign Body Collagen

UNRESTRICTED

Advisors/Committee Members: Murphy-Ullrich, Joanne E., Kabarowski, Janusz H. S.<br>, Kucik, Dennis F.<br>, Szutl, Elizabeth<br>, Woods, Anne.

Subjects/Keywords: Anoikis  – physiology<; br>; Calreticulin  – metabolism<; br>; Fibroplasts  – metabolism<; br>; Mice, Knockout<; br>; Receptors, LDL  – agonists<; br>; Thrombospondin 1  – pharmacology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Sweetwyne, M. T. (2009). Regulation of tissue remodeling through the calreticulin binding domain of thrombospondin-1. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,747

Chicago Manual of Style (16th Edition):

Sweetwyne, Mariya T. “Regulation of tissue remodeling through the calreticulin binding domain of thrombospondin-1.” 2009. Doctoral Dissertation, University of Alabama – Birmingham. Accessed October 22, 2019. http://contentdm.mhsl.uab.edu/u?/etd,747.

MLA Handbook (7th Edition):

Sweetwyne, Mariya T. “Regulation of tissue remodeling through the calreticulin binding domain of thrombospondin-1.” 2009. Web. 22 Oct 2019.

Vancouver:

Sweetwyne MT. Regulation of tissue remodeling through the calreticulin binding domain of thrombospondin-1. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2009. [cited 2019 Oct 22]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,747.

Council of Science Editors:

Sweetwyne MT. Regulation of tissue remodeling through the calreticulin binding domain of thrombospondin-1. [Doctoral Dissertation]. University of Alabama – Birmingham; 2009. Available from: http://contentdm.mhsl.uab.edu/u?/etd,747

2. Parks, Brian W. Modulation of lipoprotein metabolism and atherosclerosis by the G protein-coupled receptor, G2A.

Degree: PhD, 2008, University of Alabama – Birmingham

The G protein-coupled receptor, G2A, is expressed by multiple cell-types involved in atherosclerosis and is activated by structurally related lysophospholipids generated during low-density lipoprotein (LDL) oxidation and cholesterol esterification on circulating high-density lipoprotein (HDL) particles. In vitro studies have demonstrated that G2A mediates multiple biological responses relevant to atherosclerosis, including macrophage chemotaxis and apoptosis. To determine the role of these G2Amediated effects in atherosclerosis, we generated hypercholesterolemic G2A deficient (G2A-/-) and G2A sufficient (G2A+/+) LDL receptor knockout (LDLR-/-) mice, a commonly used hypercholesterolemic model of atherogenesis. Although G2A deficiency resulted in slight reductions in lesional macrophage apoptosis at the aortic root without affecting lesion size during early stages of atherogenesis, the major impact of G2A deletion throughout the entire aorta at early and later stages of atherogenesis was a robust reduction in lesion size. Although consistent with the loss of G2A chemotactic function, suppression of atherosclerosis in G2A-/-LDLR-/- mice was associated with increased circulating numbers of apolipoprotein E (apoE)-containing HDL particles. The ability of G2A inactivation to raise HDL in hypercholesterolemic LDLR-/- mice was dependent on apoE expression. In addition, G2A deletion failed to raise HDL levels in apoE knockout (apoE-/-) mice and consequently did not suppress atherosclerosis, irrespective of gender or the type of diet intervention. Hepatocytes, the primary cell-type responsible for HDL biogenesis, were found to express G2A and hepatocytes from hypercholesterolemic G2A-/-LDLR-/- mice secreted significantly more apoE-containing HDL particles compared to those from their G2A+/+LDLR-/- counterparts. This occurred in the absence of any significant alterations in the expression of genes encoding apoE and other key regulators of HDL metabolism. Collectively, these studies demonstrate that G2Amediated chemotaxis does not play a role in vivo during atherogenesis and establish a novel apoE-dependent mechanism mediated by G2A to control HDL biogenesis that is required for the pro-atherogenic action of G2A.

1 online resource (xv, 132 p. : ill., digital, PDF file)

Microbiology

Joint Health Sciences

Atherosclerosis G2A Lysophosphatidylcholine

UNRESTRICTED

Advisors/Committee Members: Kabarowski, Janusz H. S., Barnum, Scott R.<br>, Kearney, John F.<br>, Li, Ling<br>, Murphy-Ullrich, Joanne E..

Subjects/Keywords: Apolipoproteins E  – metabolism<; br>; Arteriosclerosis<; br>; Bone Marrow Cells  – metabolism<; br>; Cell Cycle Proteins<; br>; Hypercholesterolemia  – metabolism<; br>; Lysophosphatidylcholines  – metabolism<; br>; Macrophages  – physiology<; br>; Receptors, G-Protein-Coupled<; br>; Receptors, LDL

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Parks, B. W. (2008). Modulation of lipoprotein metabolism and atherosclerosis by the G protein-coupled receptor, G2A. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,768

Chicago Manual of Style (16th Edition):

Parks, Brian W. “Modulation of lipoprotein metabolism and atherosclerosis by the G protein-coupled receptor, G2A.” 2008. Doctoral Dissertation, University of Alabama – Birmingham. Accessed October 22, 2019. http://contentdm.mhsl.uab.edu/u?/etd,768.

MLA Handbook (7th Edition):

Parks, Brian W. “Modulation of lipoprotein metabolism and atherosclerosis by the G protein-coupled receptor, G2A.” 2008. Web. 22 Oct 2019.

Vancouver:

Parks BW. Modulation of lipoprotein metabolism and atherosclerosis by the G protein-coupled receptor, G2A. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2008. [cited 2019 Oct 22]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,768.

Council of Science Editors:

Parks BW. Modulation of lipoprotein metabolism and atherosclerosis by the G protein-coupled receptor, G2A. [Doctoral Dissertation]. University of Alabama – Birmingham; 2008. Available from: http://contentdm.mhsl.uab.edu/u?/etd,768

3. Nick, Heidi Jean. Differential contributions of c-Kit activating mutations to promotion of AML1-ETO associated neoplasia.

Degree: PhD, 2011, University of Alabama – Birmingham

The t(8;21) translocation, which generates an AML1-ETO fusion protein (also known as RUNX1-ETO), is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML). Murine studies have demonstrated that AML1-ETO promotes the accumulation of myeloid progenitor cells with self-renewal capability and impaired differentiation capacity. However, AML1-ETO+ mice do not progress to AML in the ab-sence of additional mutations, suggesting that expression of the translocation is insuffi-cient for leukemogenesis. This hypothesis is supported by studies demonstrating the per-sistence of AML1-ETO-expressing hematopoietic progenitors obtained from patients in long-term clinical remission. Mutations affecting receptor tyrosine kinases, particularly c-KIT, are commonly detected in t(8;21)+ AML. In AML1-ETO+ patient samples, differing classes of activat-ing c-KIT mutations have been observed with varying prevalence. The most common (12-48%) involves mutations that occur in the activation loop of the phosphotransferase domain, like D814V, while another involves deletions within exon 8, a region mediating receptor dimerization (2-13% of cases). To formally investigate whether distinct activat-ing c-Kit mutations differ in their capacity to drive AML1-ETO-associated AML, we used a retroviral transduction strategy to co-express AML1-ETO with c-KitD814V or a rep-resentative exon 8 mutant (c-KitT417IΔ418-419) in murine bone marrow progenitor cells used to reconstitute lethally irradiated mice. Analysis of reconstituted mice showed that AML1-ETO;c-KitD814V co-expression resulted in three non-overlapping phenotypes. In 45% of animals, an AML of relatively short latency and frequent granulocytic sarcoma was noted. Other mice exhibited a rapidly fatal myeloproliferative neoplasm (35%) or a lethal, short-latency pre-B-cell leukemia (20%). In contrast, AML1-ETO;c-KitT417IΔ418-419 co-expression promoted exclusively AML in a fraction (51%) of reconstituted mice with a median latency nearly double that observed in AML1-ETO;c-KitD814V mice that developed AML. Analysis of clonality indicated that acquisition of oncogenic events in addition to AML1-ETO and an activated c-Kit receptor were necessary for transforma-tion in all cases. The neoplastic phenotype differences between AML1-ETO;c-KitD814V and AML1-ETO;c-KitT417IΔ418-419 mice indicate that distinct activating c-Kit mutants dif-fer in leukemogenic potential, which could account for the disparity in prevalence of each c-KIT mutation concurrent with AML1-ETO in human AML.

1 online resource (xi, 98 p. : ill., digital, PDF file)

Microbiology;

Joint Health Sciences;

acute myeloid leukemia AML1-ETO c-Kit hematopoiesis

UNRESTRICTED

Advisors/Committee Members: Klug, Christopher A., Justement, Louis B.<br>, Kabarowski, Janusz H. S.<br>, Lopez, Richard D.<br>, Ryan, Thomas M..

Subjects/Keywords: Chromosomes, Human, Pair 21<; br>; Chromosomes, Human, Pair 8<; br>; DNA Mutational Analysis<; br>; Leukemia, Myeloid, Acute  – genetics<; br>; Proto-Oncogene Proteins c-kit  – genetics<; br>; Translocation, Genetic

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Nick, H. J. (2011). Differential contributions of c-Kit activating mutations to promotion of AML1-ETO associated neoplasia. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,883

Chicago Manual of Style (16th Edition):

Nick, Heidi Jean. “Differential contributions of c-Kit activating mutations to promotion of AML1-ETO associated neoplasia.” 2011. Doctoral Dissertation, University of Alabama – Birmingham. Accessed October 22, 2019. http://contentdm.mhsl.uab.edu/u?/etd,883.

MLA Handbook (7th Edition):

Nick, Heidi Jean. “Differential contributions of c-Kit activating mutations to promotion of AML1-ETO associated neoplasia.” 2011. Web. 22 Oct 2019.

Vancouver:

Nick HJ. Differential contributions of c-Kit activating mutations to promotion of AML1-ETO associated neoplasia. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2011. [cited 2019 Oct 22]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,883.

Council of Science Editors:

Nick HJ. Differential contributions of c-Kit activating mutations to promotion of AML1-ETO associated neoplasia. [Doctoral Dissertation]. University of Alabama – Birmingham; 2011. Available from: http://contentdm.mhsl.uab.edu/u?/etd,883

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