Mechanisms of aortopathy in LRP1 deficiency

LRP1 缺乏导致主动脉病的机制

基本信息

批准号：
9888522
负责人：
Areck A Ucuzian
金额：
$ 16.32万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-10 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888522
关键词：
Abdomen Abdominal Aortic Aneurysm Acute Address Aerobic Exercise Aldehydes Aminopropionitrile Aneurysm Animal Model Aortic Aneurysm Aortic Diseases Attenuated Baltimore Biology Biomechanics Blood Pressure Blood Vessels Cessation of life Chest Chronic Collagen Copper Country Data Deposition Development Disease Dissection Doctor of Philosophy Drug usage Elastin Enzymes Event Exercise Extracellular Matrix Focal Adhesions Foundations Gene Mutation Genes Genetic Genetic Determinism Goals Heart Rate Homeostasis Human Inflammatory Inflammatory Infiltrate Knowledge LDL-Receptor Related Protein 1 LDL-Receptor Related Proteins Lysine Maintenance Marfan Syndrome Maryland Mediating Mentorship Modeling Molecular Mus Muscle Contraction Pathogenesis Pathway interactions Patients Peptide Hydrolases Physicians Platelet-Derived Growth Factor Prevention Process Protein-Lysine 6-Oxidase Proteomics Pulse Pressure Regulation Research Personnel Role Scientist Severities Signal Pathway Signal Transduction Smooth Muscle Myocytes Study Subject Thoracic Aortic Aneurysm Transforming Growth Factor beta United States Universities Vascular Diseases Vascular Smooth Muscle age group crosslink exercise intervention experience extracellular human subject improved insight mouse model novel pilot trial prevent protective factors protein degradation shear stress skills treadmill

项目摘要

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.

项目概要/摘要主动脉夹层和动脉瘤疾病分别导致美国 10,000 多人死亡与西方国家所有死亡人数的 1-2% 一致，该研究表明严格的监管。 TGFβ信号通路对于血管发育和血管壁的维护至关重要，我们的初步数据表明该通路的过度活跃会导致主动脉病。蛋白质组数据表明，两种动脉瘤和夹层动物模型中 PDGF 通路被激活。 Ucuzian 实验室在 Strickland 博士的指导下，利用了两种主动脉疾病小鼠模型。确定与主动脉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 (LRP1) 缺陷模型；以及 2) 使用该药物的赖氨酰氧化酶 (LOX) 抑制模型 Ucuzian 和 Strickland 实验室令人兴奋的初步数据发现了一种新型的 -氨基丙腈 (BAPN)。发现轻度有氧运动可减轻与 smLRP1 缺乏和 LOX 相关的主动脉病该提案的目的是研究动脉瘤和抑制的分子机制。解剖发展，并研究运动干预以减弱这些过程，我们将利用这两者。主动脉病小鼠模型和人类受试者研究来解决这些问题。具体目标 1. 使用两只小鼠确定主动脉疾病发生的机制主动脉病模型的假设是smLRP1 和LOX 可以防止主动脉的发展。通过减弱 TGF 和/或 PDGF 介导的信号事件来治疗动脉瘤和夹层。具体目标 2. 确定轻度有氧运动减弱发展的机制使用两种主动脉病小鼠模型研究主动脉疾病。假设运动可以预防主动脉疾病。通过减弱 TGF 和/或 PDGF 介导的信号事件来形成动脉瘤和夹层。具体目标 3. 确定出现上升的患者中失调的分子途径主动脉瘤和 A 型夹层的主要假设是 TGF 信号传导将被激活。在患有胸动脉瘤和夹层的人类受试者中，第二个假设是这些通路紊乱的存在与主动脉疾病的严重程度和程度相关推介会。实习生 Areck Ucuzian 博士的长期目标是成为一名独立的医师科学家他的短期目标是培养血管生物学领域所需的技能和经验。研究员成为一名独立的临床医生-研究者当前的提案特别关注于血管壁稳态的基本机制可预防多种血管疾病。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)，在 Dudley Strickland 博士的指导下。