Vascular Smooth Muscle Cells and Elastolysis in Abdominal Aortic Aneurysms

腹主动脉瘤中的血管平滑肌细胞和弹性组织溶解

• 批准号: 7315869
• 负责人: JOHN A CURCI
• 金额: $ 12.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315869
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Advisory Committees; Affect; Aneurysm; Aorta; Aortic Aneurysm; Aortic Diseases; Aortic Rupture; Arterial Fatty Streak; Atherosclerosis; Biology; Blood Vessels; Cause of Death; Cell Differentiation process; Cell physiology; Cells; Cessation of life; Characteristics; Coculture Techniques; Condition; Conditioned Culture Media; Deposition; Detection; Development; Disease; Distal; Education; Elastic Fiber; Elastin; Elderly; Elderly man; Endopeptidases; Environment; Exhibits; Extracellular Matrix; Failure; Functional disorder; Goals; Growth; Human; Hyperplasia; In Vitro; Inflammatory; Investigation; Knowledge; Lesion; Maintenance; Matrix Metalloproteinases; Medial; Mediating; Mentorship; Metabolism; Metalloproteases; Microarray Analysis; Molecular Profiling; Morphology; Pathologic; Pathological Dilatation; Pathology; Pathway interactions; Pattern; Peptide Hydrolases; Performance; Phenotype; Population; Principal Investigator; Production; Protease Inhibitor; Proteins; Proteolysis; Radiolabeled; Recruitment Activity; Regulation; Relative (related person); Research; Research Design; Research Personnel; Research Training; Role; Rupture; Smooth Muscle Myocytes; Structure; Surgeon; Techniques; Therapeutic Intervention; Tissues; Trees; Tunica Adventitia; United States; Universities; Vascular Diseases; Washington; Work; abstracting; authority; base; cDNA Arrays; career; design; improved; in vitro Model; laser capture microdissection; macrophage; male; medical schools; novel; novel strategies; novel therapeutics; prevent; programs; proteinase In; radiotracer; response; skills; success

DESCRIPTION (provided by applicant): This proposal defines a 5 year program of education and research designed to establish the independence of the principal investigator in a career as an academic vascular surgeon. The education component builds on vascular research training successfully completed as a resident at the Washington University School of Medicine. The research component of this program is designed to develop the practical skills necessary for a productive research career as well as establish independent success in a novel approach to the study of abdominal aortic aneurysms. Dr. Robert Thompson will provide coordinated mentorship and expertise in aneurysm pathology. The advisory committee is similarly comprised of very successful researchers and authorities including Dr. Stephen Schwartz who will provide support for the biology of vascular smooth muscle cells along with Dr. Robert Mecham who will support the studies in elastin metabolism. Dr. J. Perren Cobb's proficiency in performance and analysis of microarrarys will provide critical assistance with the expression studies. These studies will focus on the vascular smooth muscle cell (SMC) and its unique role in the characteristic pathologic changes of abdominal aortic aneurysms (AAA), particularly the loss of medial elastic fiber. Under normal conditions these cells are critical for the production and maintenance of the arterial wall extracellular matrix, and abnormal function of these cells is central to other aortic diseases such as atherosclerosis. Because we have observed unique characteristics and elastolytic activities of these cells in vitro and m vivo, we believe that these cells are phenotypically unique and that these changes support the development of an elastolysis characteristic of AAA. These investigations will compare aneurysm SMC to SMC from normal aorta and atherosclerotic plaque to i) determine if vascular SMC derived from human AAA tissues exhibit a unique differentiation phenotype compared to SMC derived from atherosclerotic plaque and normal aorta, 2) characterize the expression and regulation of elastolytic proteases and protease inhibitors by aneurysm cells compared to normal and atherosclerotic cells, and 3) determine whether aneurysm SMC are uniquely capable in mediating elastic fiber degeneration compared to non-aneurysmal vascular SMC. The abdominal aortic aneurysm is a silent, progressive and ultimately deadly weakening of the aortic wall that affects a large proportion of the elderly male population. Despite a long incubation period and easy means of detection, no pharmacologic therapy currently exists to prevent progression of small aortic aneurysms due to an incomplete understanding of the pathophysiology. The goal of these studies is to open the door for new therapeutics by developing an understanding of the role of the resident smooth muscle cell on this arterial wall failure. (End of Abstract)

描述（由申请人提供）： 该提案定义了一个为期5年的教育和研究计划，旨在建立主要研究者在学术血管外科医生职业生涯中的独立性。教育部分建立在血管研究培训成功完成作为住院医师在华盛顿大学医学院。该计划的研究部分旨在培养富有成效的研究生涯所需的实践技能，并在腹主动脉瘤研究的新方法中取得独立成功。罗伯特·汤普森博士将提供动脉瘤病理学方面的协调指导和专业知识。咨询委员会同样由非常成功的研究人员和权威人士组成，包括Stephen Schwartz博士，他将为血管平滑肌细胞的生物学提供支持沿着Robert Mecham博士将支持弹性蛋白代谢的研究。J. Perren Cobb博士在微阵列性能和分析方面的熟练程度将为表达研究提供关键帮助。这些研究将集中于血管平滑肌细胞（SMC）及其在腹主动脉瘤（AAA）特征性病理变化中的独特作用，特别是中膜弹性纤维的丢失。在正常情况下，这些细胞对于动脉壁细胞外基质的产生和维持至关重要，并且这些细胞的异常功能对于其他主动脉疾病如动脉粥样硬化是重要的。由于我们在体外和体内观察到这些细胞的独特特征和弹性蛋白溶解活性，我们认为这些细胞在表型上是独特的，这些变化支持AAA弹性蛋白溶解特征的发展。这些研究将比较动脉瘤SMC与来自正常主动脉和动脉粥样硬化斑块的SMC，以i）确定与来自动脉粥样硬化斑块和正常主动脉的SMC相比，来自人AAA组织的血管SMC是否表现出独特的分化表型，2）表征与正常和动脉粥样硬化细胞相比，动脉瘤细胞对弹性蛋白分解蛋白酶和蛋白酶抑制剂的表达和调节，和3）确定与非动脉瘤血管SMC相比，动脉瘤SMC是否具有独特的介导弹性纤维变性的能力。腹主动脉瘤是一种无症状的，渐进的，最终致命的主动脉壁弱化，影响了很大一部分老年男性人口。尽管潜伏期较长且易于检测，但由于对病理生理学的不完全理解，目前还没有药物治疗来预防小主动脉瘤的进展。这些研究的目的是 通过了解平滑肌细胞在动脉壁衰竭中的作用，为新的治疗方法打开了大门。 (End摘要）