Mechanisms of aortopathy in LRP1 deficiency

项目概要/摘要 在美国，主动脉夹层和动脉瘤疾病各导致超过10，000例死亡 在西方国家，死亡人数占所有死亡人数的1-2%。与之前的研究一致，这些研究表明， TGFβ信号通路的激活对血管发育和血管壁的维持至关重要， 我们的初步数据表明，该途径的过度活跃有助于脊椎病。此外，我们的初步 蛋白质组学数据提示在动脉瘤和夹层的两种动物模型中PDGF β通路的激活。 在Strickland博士的指导下，Ucuzian实验室利用了两种主动脉疾病的小鼠模型 确定与前列腺病相关的几种失调途径：1）平滑肌细胞特异性LDL 受体相关蛋白1（LRP 1）缺乏模型;和2）使用所述药物的赖氨酰氧化酶（LOX）抑制模型 N-氨基丙腈（BAPN）。Ucuzian和Strickland实验室的令人兴奋的初步数据已经确定了一种新的 发现轻度有氧运动可以减轻与smLRP 1缺乏和LOX相关的动脉粥样硬化 抑制作用本提案的目的是研究动脉瘤和 解剖发展，并调查运动干预，以减轻这些过程。我们将利用两者 一个老鼠的脊椎病模型和一个人类的主题研究来解决这些问题。 具体目标1。使用两种小鼠来确定主动脉疾病发展的潜在机制， 脊椎病的模型假设smLRP 1和LOX可以防止主动脉粥样硬化的发展。 通过减弱TGF β 1和/或PDGF β 2介导的信号传导事件来治疗动脉瘤和夹层。 具体目标2。为了确定轻度有氧运动减弱以下发展的机制， 主动脉疾病，使用两种小鼠动脉疾病模型。假设是运动可以防止主动脉 通过减弱TGF β和/或PDGF β介导的信号传导事件来形成动脉瘤和夹层。 具体目标3。为了确定上行性前列腺癌患者中失调的分子通路， 主动脉瘤和A型夹层。主要假设是TGF β 1信号传导将被激活， 在患有胸部动脉瘤和夹层的人类受试者中。次要假设是， 这些通路干扰的存在将与主动脉疾病的严重程度和范围相关 演示文稿. 实习生阿雷克·乌库齐安博士的长期目标是成为一名独立的医生兼科学家 在血管生物学领域。他的短期目标是培养一个人所需的技能和经验。 成为一名独立的临床研究员。目前的建议特别侧重于一个 血管壁稳态的基本机制，可预防多种血管疾病。的 本研究的目的计划在血管和炎症性疾病中心（CVID）完成 和马里兰州，巴尔的摩（UMB）的指导下，博士达德利斯特里克兰，博士。

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.