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You searched for +publisher:"University of Cincinnati" +contributor:("Molkentin, Jeffery"). Showing records 1 – 3 of 3 total matches.

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University of Cincinnati

1. Schwanekamp, Jennifer A. Dissecting the Roles of Periostin and TGFBI in Cardiovascular Disease.

Degree: PhD, Medicine: Molecular Genetics, Biochemistry, & Microbiology, 2017, University of Cincinnati

Deposition, maturation, and regulation of the extracellular matrix (ECM) are key components of the overall fibrotic response, which plays a major pathological role in many forms of cardiovascular disease (CVD). Paradoxically, ECM remodeling is also required for preserving ventricular chamber integrity after injury and for maintaining vessel compliance and structure under physiological conditions. However, excessive and dysregulated ECM deposition occurs during disease, such as vessel wall remodeling during atherosclerosis or the replacement of dying cardiomyocytes by noncompliant scar tissue in the setting of myocardial infarction (MI). Although the molecular players that regulate pathological ECM remodeling are still poorly understood, one superfamily known as the matricellular proteins, a group of stress-induced ECM modulators, has received particular attention.Here we investigated the roles played by two matricellular protein family members, periostin and transforming growth factor beta induced (TGFBI), in mouse models of atherosclerosis, coronary artery disease (CAD) and hypertensive heart disease (HHD). Periostin and TGFBI are known to interact directly with a number of ECM proteins and have roles in cell adhesion and migration, two essential components of the fibrotic response. We first investigated the role periostin plays in atherosclerotic plaque development. Using a well-characterized model of atherosclerosis, the ApoE knockout mouse (ApoE-/-), we show that periostin is induced within the plaque and also in the circulating blood, suggesting a role for periostin in disease progression. Using a periostin-deficient global knockout mouse model crossed to the ApoE-/- mouse, we find that loss of periostin reduces plaque burden through a mechanism involving decreased collagen maturation within the plaque and impaired macrophage recruitment. We then investigated the role of TGFBI, a paralog of periostin, in ventricular remodeling in the heart after injury. Because periostin and TGFBI share significant structural and amino acid similarity, we hypothesized that TGFBI may have overlapping functions with periostin. To test this, we used a mouse model with genetic deletion of TGFBI and found that loss of this gene did not alter disease pathology after MI, suggesting that periostin may be able to compensate for loss of TGFBI. To further test this, we generated mice deficient for both TGFBI and periostin; however, combined deletion of TGFBI and periostin did not worsen disease pathology after MI beyond what was observed with periostin deletion, suggesting that periostin is the main indicator of pathological remodeling after injury in the heart. The data presented in this thesis suggest that periostin is not only a main effector in ECM remodeling in the heart in response to injury, but that it also plays a dominant role over TGFBI, in addition to being a significant contributor to atherosclerotic disease progression. Future studies that dissect the regulatory elements that control expression of periostin or TGFBI in… Advisors/Committee Members: Molkentin, Jeffery (Committee Chair).

Subjects/Keywords: Molecular Biology; extracellular matrix; cardiovascular disease; atherosclerosis; periostin; TGFBI; fibrosis

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APA (6th Edition):

Schwanekamp, J. A. (2017). Dissecting the Roles of Periostin and TGFBI in Cardiovascular Disease. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803264229101

Chicago Manual of Style (16th Edition):

Schwanekamp, Jennifer A. “Dissecting the Roles of Periostin and TGFBI in Cardiovascular Disease.” 2017. Doctoral Dissertation, University of Cincinnati. Accessed November 16, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803264229101.

MLA Handbook (7th Edition):

Schwanekamp, Jennifer A. “Dissecting the Roles of Periostin and TGFBI in Cardiovascular Disease.” 2017. Web. 16 Nov 2019.

Vancouver:

Schwanekamp JA. Dissecting the Roles of Periostin and TGFBI in Cardiovascular Disease. [Internet] [Doctoral dissertation]. University of Cincinnati; 2017. [cited 2019 Nov 16]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803264229101.

Council of Science Editors:

Schwanekamp JA. Dissecting the Roles of Periostin and TGFBI in Cardiovascular Disease. [Doctoral Dissertation]. University of Cincinnati; 2017. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803264229101

2. Millay, Douglas P. Calcium as the central mediator of muscle dysfunction due to muscular dystrophy.

Degree: PhD, Medicine : Molecular Genetics, Biochemistry, and Microbiology, 2008, University of Cincinnati

Muscular dystrophy (MD) is a debilitating genetic disorder affecting cardiac and skeletal muscle that typically results in loss of ambulation in the teen years and death in the second or third decade of life. The gene disruptions that cause this muscle wasting disease have been known for over 20 years and most encode proteins which reside in a large complex known as the dystrophin-glycoprotein complex (DGC). The function of the DGC is to provide structural support to the sarcolemma (muscle cell membrane) effectively reducing membrane damage after contraction. In the absence of a functional DGC, contraction-induced lesions in the sarcolemma occur and this is hypothesized to initiate MD disease progression. Destabilization of the membrane is proposed to cause the unregulated entry of calcium into the myofiber, possibly causing degeneration of the fiber. Despite good evidence that calcium levels are altered in dystrophic myotubes, at least in the subsarcolemmal space, there is a lack of knowledge concerning the pathways by which this intracellular calcium results in degeneration. Moreover, there are currently no studies directly implicating calcium as the disease-inducing molecule in MD. Here, we present data suggesting that mitochondria are one sensor of this increased calcium and respond by undergoing mitochondrial permeability transition (MPT) resulting in necrosis of the myofiber. To test this hypothesis we crossed animals lacking cyclophilin D (CypD, Ppif gene), a critical regulator of MPT, with two MD models. In both cases, mice lacking the extracellular matrix protein lamanin-2a (Lama2-/-) or the DGC protein d-sarcoglycan (Scgd-/-) along with Ppif exhibited a reduction in disease characteristics compared to the same animals with normal levels of CypD. Specifically, mitochondria from muscle of the MD mice were swollen and genetic loss of Ppif rescued this phenotype, inhibiting MPT and ultimately reducing disease through a mitochondrial-dependent mechanism. This led us to test the efficacy of a CypD inhibitor, Debio-025, in its ability to block MPT and attenuate disease progression. Indeed, Scgd-/- and mdx (mouse model lacking dystrophin) mice treated with Debio-025 for 6 weeks showed a lessening of disease characteristics compared to vehicle-treated controls. Thus, MPT inhibition with Debio-025 is a novel treatment strategy in MD. Lastly, we tested whether calcium can cause a MD-like phenotype without a mutation in the DGC by transgenic overexpression of ion channels in skeletal muscle. Both sodium-calcium exchanger and transient receptor potential of the canonical class (TRPC3) transgenic animals display skeletal muscle disease suggesting calcium does contribute to the disease in MD. We have shown that inhibition of the calcium-sensitive MPT process reduces MD disease and increased intracellular calcium, independent of an unstable sarcolemma, results in disease similar to MD. Collectively, these results strongly suggest calcium is the central mediator of MD pathogenesis. Advisors/Committee Members: Molkentin, Jeffery (Committee Chair).

Subjects/Keywords: Molecular Biology; muscular dystrophy; calcium; mitochondrial permeability transition; cyclophilin D

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

APA (6th Edition):

Millay, D. P. (2008). Calcium as the central mediator of muscle dysfunction due to muscular dystrophy. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211297412

Chicago Manual of Style (16th Edition):

Millay, Douglas P. “Calcium as the central mediator of muscle dysfunction due to muscular dystrophy.” 2008. Doctoral Dissertation, University of Cincinnati. Accessed November 16, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211297412.

MLA Handbook (7th Edition):

Millay, Douglas P. “Calcium as the central mediator of muscle dysfunction due to muscular dystrophy.” 2008. Web. 16 Nov 2019.

Vancouver:

Millay DP. Calcium as the central mediator of muscle dysfunction due to muscular dystrophy. [Internet] [Doctoral dissertation]. University of Cincinnati; 2008. [cited 2019 Nov 16]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211297412.

Council of Science Editors:

Millay DP. Calcium as the central mediator of muscle dysfunction due to muscular dystrophy. [Doctoral Dissertation]. University of Cincinnati; 2008. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211297412


University of Cincinnati

3. Wilkins, Benjamin Joseph. Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health?.

Degree: PhD, Medicine : Molecular and Developmental Biology, 2004, University of Cincinnati

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the developed world. One form of CVD, congestive heart failure, is often preceded by a pathologic hypertrophy of the heart and is predicted to become an increasing public health problem. In order to identify new targets for intervention in these processes, a great deal of investigation has been dedicated to elucidating the molecular regulatory circuits involved in the development of cardiac hypertrophy. Recently, signaling through the calcium-activated phosphatase calcineurin has been implicated as a necessary and sufficient mediator of cardiac hypertrophy in a variety of animal models. However, the downstream effectors necessary for calcineurin-induced hypertrophy have not been determined, and the exact spatiotemporal stimuli that activate this signaling pathway are still a matter of debate. Here, we present evidence that the transcription factor, nuclear factor of activated T cells (NFAT) plays a critical role in calcineurin-mediated cardiac hypertrophic signaling. Analysis of gene-targeted mice revealed that NFATc3 is necessary for a full response to angiotensin II, pressure-overload, or calcineurin-induced cardiac hypertrophy, while the related factor NFATc4 is dispensable for the same responses. In addition, analysis of transgenic mice carrying a NFAT reporter construct indicated that while cardiac NFAT activity increases in a delayed and sustained manner in response to pressure overload-induced pathologic hypertrophy and infarct-induced heart failure, three models of physiologic hypertrophy fail to increase reporter activity over control levels. Taken together, these results indicate that the calcineurin-NFAT signaling module may be adapted specifically for transducing pathologic signals into a hypertrophic response in the heart, and validate NFAT factors as potential therapeutic targets for intervention in a number of cardiovascular disease processes. Future work will focus on elucidating the upstream calcium sources that induce calcineurin-NFAT activation in the heart, as well as how this pathway interacts with other intracellular signal transducers to produce a coordinated hypertrophic response to pathologic stimuli. Advisors/Committee Members: Molkentin, Jeffery (Advisor).

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

APA (6th Edition):

Wilkins, B. J. (2004). Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health?. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1088446389

Chicago Manual of Style (16th Edition):

Wilkins, Benjamin Joseph. “Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health?.” 2004. Doctoral Dissertation, University of Cincinnati. Accessed November 16, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1088446389.

MLA Handbook (7th Edition):

Wilkins, Benjamin Joseph. “Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health?.” 2004. Web. 16 Nov 2019.

Vancouver:

Wilkins BJ. Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health?. [Internet] [Doctoral dissertation]. University of Cincinnati; 2004. [cited 2019 Nov 16]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1088446389.

Council of Science Editors:

Wilkins BJ. Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health?. [Doctoral Dissertation]. University of Cincinnati; 2004. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1088446389

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