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: 8113406
• 负责人: JOHN A CURCI
• 金额: $ 12.14万
• 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/8113406
• 关键词: AT-Hook Motifs; 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; Conditioned Culture Media; Deposition; Detection; Development; Disease; Distal; Education; Elastic Fiber; Elastin; Elderly; Elderly man; 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)： 这项建议明确了一个为期5年的教育和研究计划，旨在确立首席研究人员在作为学术血管外科医生的职业生涯中的独立性。教育部分建立在作为华盛顿大学医学院住院医生时成功完成的血管研究培训基础上。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方面取得独立成功。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，其中包括斯蒂芬·施瓦茨博士和罗伯特·梅查姆博士。施瓦茨博士将为血管平滑肌细胞生物学提供支持，罗伯特·梅查姆博士将支持弹性蛋白代谢研究。J.Perren Cobb博士在微阵列的性能和分析方面的熟练程度将为表达研究提供关键的帮助。这些研究将集中在血管平滑肌细胞(SMC)及其在腹主动脉瘤(AAA)特征性病理变化中的独特作用，特别是中层弹性纤维的丢失。在正常情况下，这些细胞对动脉壁细胞外基质的产生和维持至关重要，而这些细胞的异常功能是其他主动脉疾病(如动脉粥样硬化)的核心。由于我们在体外和体内观察到了这些细胞的独特特性和弹性溶解活性，我们认为这些细胞是独特的表型，这些变化支持AAA弹性溶解特性的发展。这些研究将对动脉瘤SMC和正常动脉及动脉粥样硬化斑块的SMC进行比较，以1)确定来源于人AAA组织的血管SMC是否显示出与来自动脉粥样硬化斑块和正常主动脉的SMC相比的独特的分化表型；2)表征动脉瘤细胞与正常和动脉粥样硬化细胞相比弹性蛋白水解酶和蛋白酶抑制物的表达和调节；以及3)确定与非动脉瘤样血管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声的、进行性的、最终致命的主动脉壁变弱，影响到很大比例的老年男性人口。尽管潜伏期长，检测手段简单，但由于对病理生理学的不完全了解，目前尚无药物治疗方法来预防小主动脉瘤的进展。这些研究的目的是通过了解驻留的平滑肌细胞在动脉壁衰竭中的作用，为新的治疗方法打开大门。 (摘要结束)

项目成果

A randomized, placebo-controlled trial of doxycycline after endoluminal aneurysm repair.

• DOI: 10.1016/j.jvs.2008.03.064
• 发表时间: 2008-09
• 期刊: JOURNAL OF VASCULAR SURGERY
• 影响因子: 4.3
• 作者: Hackmann, Amy E.;Rubin, Brian G.;Sanchez, Luis A.;Geraghty, Patrick A.;Thompson, Robert W.;Curci, John A.
• 通讯作者: Curci, John A.

Digging in the "soil" of the aorta to understand the growth of abdominal aortic aneurysms.

• DOI: 10.2310/6670.2008.00085
• 发表时间: 2009-05
• 期刊: Vascular
• 影响因子: 1.1
• 作者: Curci JA