Genomics of Peripheral Arterial Disease

外周动脉疾病的基因组学

• 批准号: 6908725
• 负责人: Jeffrey H. Lawson
• 金额: $ 15.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-06 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908725
• 关键词: amputation; aorta disorder; artery occlusion; atherosclerosis; biotechnology; clinical research; comparative genomic hybridization; data collection; gene expression profiling; genetic registry /resource /referral center; genome; human subject; human tissue; information retrieval; microarray technology; molecular biology information system; pathologic process; peripheral blood vessel disorder; phenotype; statistics /biometry

DESCRIPTION (provided by applicant): Peripheral arterial disease (PAD) is a complex illness causing a significant amount of pain and suffering, with an estimated 8-12 million cases in the United States. The elderly are particularly at risk, with a prevalence of approximately 20% in people greater than 75 years of age. Further, the number of cases is expected to increase as the population ages. PAD exerts significant effects on functional capacity, quality of life, productivity, and health care costs. This R21 Grant application was developed to address the genetic basis of PAD using existing and novel data sets and tissue samples. Recent sequencing of the human genome has opened up fertile areas of investigation for many human diseases. To date, there have been a limited number of studies that have investigated the genetic underpinnings of PAD. Fundamental advancements in our knowledge of the molecular pathophysiology of PAD utilizing genome technologies represents an unprecedented opportunity to develop new diagnostic, prognostic and therapeutic interventions for this disease. To address this problem, we have developed a unique research group that combines the collaborative expertise of vascular surgery, molecular cardiology, biostatistics, and human genetics. In this application we propose to investigate PAD using genomic methodology. We have assembled all of the necessary components with direct access to human peripheral arteries, a large clinical population with PAD, experience with gene expression profiling, and the advanced statistical analysis required to study this complex disease. Using this methodology, we propose to use expression genomic s on peripheral arterial tissue collected from limb amputations in patients with severe PAD. Using data derived from these arterial samples we will test the following hypotheses: 1. Gene expression profiles of peripheral arterial tissues can be used to identify molecular phenotypes of diseased arteries. 2. Various phenotypes of patients with PAD will have different patterns of gene expression. 3 Genes isolated from diseased peripheral arteries will differ from key genes that have been identified from existing data sets for central (aortic) atherosclerosis. To achieve these goals, the following specific aims will be pursued: 1. To isolate arterial tissue from amputated limbs and collect clinical data from these patients with severe PAD. 2. To perform gene expression analysis using microarrays on RNA extracted from harvested peripheral arterial tissues. 3. To apply statistical methods to identify gene expression patterns that correlate with the clinical phenotypes of patients with PAD and compare these expression patterns to existing identified genes of aortic atherosclerosis.

描述（由申请人提供）：外周动脉疾病（PAD）是一种引起大量疼痛和痛苦的复杂疾病，在美国估计有800万至1200万例。老年人的风险尤其大，75岁以上人群的患病率约为20%。此外，随着人口老龄化，预计病例数将增加。PAD对功能能力、生活质量、生产力和医疗保健费用有显著影响。本R21拨款申请旨在利用现有和新的数据集和组织样本来解决PAD的遗传基础。最近的人类基因组测序为许多人类疾病的研究开辟了肥沃的领域。迄今为止，研究PAD遗传基础的研究数量有限。利用基因组技术，我们在PAD分子病理生理学方面的知识取得了根本性的进步，这为开发新的诊断、预后和治疗干预措施提供了前所未有的机会。为了解决这个问题，我们建立了一个独特的研究小组，结合了血管外科、分子心脏病学、生物统计学和人类遗传学的合作专业知识。在这个应用中，我们建议使用基因组方法来研究PAD。我们已经组装了所有必要的组件，可以直接进入人类外周动脉，大量的PAD临床人群，基因表达谱的经验，以及研究这种复杂疾病所需的先进统计分析。使用这种方法，我们建议在严重PAD患者截肢后收集的外周动脉组织中使用表达基因组。利用从这些动脉样本中获得的数据，我们将检验以下假设：外周动脉组织的基因表达谱可用于鉴定病变动脉的分子表型。2. 不同表型的PAD患者会有不同的基因表达模式。从病变外周动脉中分离的基因将不同于从现有中央（主动脉）动脉粥样硬化数据集中鉴定的关键基因。为实现这些目标，将追求下列具体目标：目的：分离断肢动脉组织，收集重度PAD患者的临床资料。2. 利用微阵列对采集的外周动脉组织提取的RNA进行基因表达分析。3. 应用统计学方法鉴定与PAD患者临床表型相关的基因表达模式，并将这些表达模式与现有的主动脉粥样硬化基因进行比较。