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Regulation of Collagen Fibril Structure and Function by DDR1 in the Murine Aorta

Tonniges, Jeffrey R
http://rave.ohiolink.edu/etdc/view?acc_num=osu1471373750

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Biophysics.
Collagen type 1 is the most abundant extracellular matrix protein in vertebrates. Collagen fibrils provide vital scaffolding, support, and strength to tissues as well as modulate cell-matrix interactions. The quantity and quality of collagen fibrils are important for a variety of physiological and pathological processes. Much is known about how collagen quantity impacts health and disease, but little is known about the impact of collagen quality, i.e., the collagen fibril structure. A large number of factors can cause alterations in collagen fibril structure including mutations in collagen genes, dysregulation of collagen processing enzymes, or altered expression of collagen binding proteins (CBP). Previous studies have established that the CBP, discoidin domain receptor 1 (DDR1) alters collagen fibril structure in vitro. The first aim of this thesis was to determine if DDR1 impacts collagen fibril structure in vivo. To address this question, collagen fibrils in the adventitia of DDR1 knockout (KO) mice aortas were imaged using high resolution microscopy techniques, namely transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM). The aortic adventitia of DDR1 deficient mice exhibited increased collagen deposition, a higher percentage of large diameter fibrils, and increased D-periodic depth compared to their wild-type (WT) littermates. The second aim was to determine if the structural changes in DDR1-deficient collagen fibrils have a functional consequence. Platelet-collagen adhesion has been shown to exhibit some sensitivity to the structure of collagen fibrils. Given this, we tested whether DDR1-deficient collagen fibrils impact platelet-collagen adhesion. To investigate this question, we examined the binding of human platelets and of the CBPs primarily involved in platelet-collagen interactions, i.e., glycoprotein VI (GPVI) and von Willebrand factor (VWF) to the collagen fibrils in aortic sections from DDR1-KO versus WT mice. Platelets bound significantly greater to DDR1 KO aortic collagen compared to WT aortic collagen. Additionally, VWF bound significantly more to DDR1 KO collagen, while GPVI showed a trend towards greater binding to DDR1 KO collagen. The third aim was to determine if collagen fibril structure is altered in a pathological process. Extensive collagen deposition and remodeling occurs in abdominal aortic aneurysms (AAA), which can lead to rupture of the vascular wall. Given this, we examined the collagen fibril structure in an Angiotensin-II infused mouse model of AAA using high resolution microscopy. TEM and AFM studies revealed the presence of abnormal collagen fibrils, in addition to normal fibrils, in the remodeled regions of mouse aortic aneurysms. The abnormal collagen fibrils were characterized by weakened or unresolvable D-periodic banding, wavy as opposed to straight contours, and decreased D-periodic depth. In conclusion, collagen fibril structure is an important parameter in health and disease, which can be evaluated in part by ultrastructural microscopy. Collagen fibril structure could be used as a biomarker or diagnostic criteria for pathologies. In pathologies, changes to collagen fibril structure could impact cell-matrix interactions, which could alter the progression of the disease. Finally, because expression levels of CBPs, like DDR1, alter collagen fibril structure, these proteins could be targeted in therapies to ameliorate disease progression.
Gunjan Agarwal (Advisor)
Alevriadou Barbara (Committee Member)
Gooch Keith (Committee Member)
152 p.
Biophysics; Histology; Pathology; Physiology
collagen; abdominal aortic aneurysm; discoidin domain receptor 1; aorta; collagen fibrils; collagen fibers; platelet adhesion; platelet-collagen interactions

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Citations

  • Tonniges, J. R. (2016). Regulation of Collagen Fibril Structure and Function by DDR1 in the Murine Aorta [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471373750

    APA Style (7th edition)

  • Tonniges, Jeffrey. Regulation of Collagen Fibril Structure and Function by DDR1 in the Murine Aorta. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1471373750.

    MLA Style (8th edition)

  • Tonniges, Jeffrey. "Regulation of Collagen Fibril Structure and Function by DDR1 in the Murine Aorta." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471373750

    Chicago Manual of Style (17th edition)

osu1471373750
333
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This open access ETD is published by The Ohio State University and OhioLINK.