Mechanisms of aortopathy in LRP1 deficiency

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Project Summary/Abstract Aortic dissection and aneurysmal disease accounts for over 10,000 deaths in the United States each year, and 1-2% of all deaths in Western countries. Consistent with prior studies that reveal that tight regulation of the TGFβ signaling pathways is essential for vascular development and the maintenance of the vessel wall, our preliminary data suggest overactivity of this pathway contributes to aortopathy. In addition, our preliminary proteomic data suggests activation of the PDGF pathway in two animal models of aneurysm and dissection. The Ucuzian lab, under the mentorship of Dr. Strickland, has utilized two murine models of aortic disease to identify several dysregulated pathways associated with aortopathy: 1) a smooth muscle cell specific LDL receptor-related protein 1 (LRP1) deficiency model; and 2) a lysyl oxidase (LOX) inhibition model using the drug -aminopropionitrile (BAPN). Exciting preliminary data by the Ucuzian and Strickland labs has identified a novel finding that mild aerobic exercise attenuates the aortopathy associated with both smLRP1 deficiency and LOX inhibition. The objectives of this proposal are to investigate the molecular mechanisms by which aneurysms and dissections develop, and to investigate exercise intervention to attenuate these processes. We will utilize both a mouse models of aortopathy and a human subject study to address these questions. Specific Aim 1. To define mechanisms underlying the development of aortic disease using two mouse models of aortopathy. The hypothesis is that smLRP1 and LOX protects against the development of aortic aneurysm and dissection by attenuating TGF and/or PDGF mediated signaling events. Specific Aim 2. To define mechanisms by which mild aerobic exercise attenuates the development of aortic disease using two mouse models of aortopathy. The hypothesis is that exercise prevents aortic aneurysm and dissection formation by attenuating TGF and/or PDGF mediated signaling events. Specific Aim 3. To identify dysregulated molecular pathways in patients presenting with ascending aortic aneurysms and Type A dissections. The primary hypothesis is that TGF signaling will be activated in human subjects presenting with thoracic aneurysms and dissections. The secondary hypothesis is that the presence of these pathway disturbances will correlate with the severity and extent of aortic disease presentation. The long-term goals of Dr. Areck Ucuzian, the trainee, is to become an independent physician-scientist in the field of Vascular Biology. His short-term goal is to cultivate the skills and experience required of a researcher to become an independent clinician-investigator. The current proposal focuses specifically on a fundamental mechanism of vessel wall homeostasis which prevents a broad range of vascular diseases. The Aims of this study are planned to be completed at the Center for Vascular and Inflammatory Diseases (CVID) and the University of Maryland, Baltimore (UMB) under the mentorship of Dr. Dudley Strickland, PhD.