Mechanisms of aortopathy in LRP1 deficiency

项目摘要/摘要 在美国，主动脉夹层和动脉瘤分别导致1万多人死亡 每年，占西方国家所有死亡人数的1-2%。与之前的研究一致，这些研究表明，严格的监管 转化生长因子β信号通路对血管发育和血管壁的维持是必不可少的， 我们的初步数据表明，这一途径的过度活跃导致了主动脉病变。另外，我们初步的 蛋白质组学数据表明，在两种动脉瘤和夹层动物模型中，血小板衍生生长因子通路被激活。 在斯特里克兰博士的指导下，乌库兹实验室利用了两种主动脉疾病的小鼠模型 识别与大动脉病变相关的几种失调途径：1)一种平滑肌细胞特异性低密度脂蛋白 受体相关蛋白1(LRP1)缺乏模型；以及2)使用该药物的赖氨酰氧化酶(LOX)抑制模型 氨基丙腈()。乌库兹安和斯特里克兰实验室令人兴奋的初步数据确定了一种新的 发现轻度有氧运动可减轻与smLRP1缺乏和LOX相关的大动脉病变 抑制力。这项建议的目的是研究动脉瘤和高血压的分子机制。 解剖的发展，并研究运动干预以减弱这些过程。我们将利用这两种方式 一只小鼠的大动脉病变模型和一项人类受试者研究来解决这些问题。 具体目的1.用两只小鼠确定主动脉疾病发生的机制 大动脉病变的模型。假设smLRP1和LOX可以预防主动脉的发育 通过减弱转化生长因子和/或血小板衍生生长因子介导的信号事件而导致动脉瘤和夹层。 具体目标2.确定轻度有氧运动延缓糖尿病发展的机制 采用两种小鼠主动脉病变模型。假设是运动可以预防大动脉 通过减弱转化生长因子和/或血小板衍生生长因子介导的信号事件而形成动脉瘤和夹层。 具体目的3.确定表现为上行性疾病的患者中的失调分子通路 主动脉瘤和A型夹层。初步的假设是转化生长因子信号将被激活 在表现为胸部动脉瘤和夹层的人类受试者中。第二个假设是 这些通路障碍的存在将与主动脉疾病的严重程度和程度相关。 演示文稿。 实习医生Areck Ucuzian的长期目标是成为一名独立的内科科学家 在血管生物学领域。他的短期目标是培养一名 研究人员成为一名独立的临床医生兼研究员。目前的提案特别侧重于 血管壁动态平衡的基本机制，可预防多种血管疾病。这个 这项研究的目标计划在血管和炎症疾病中心(CVID)完成 和马里兰大学巴尔的摩分校(UMB)，由Dudley Strickland博士博士指导。

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.