Genetics of In-Stent Restenosis: The Human Strategy

应聘者描述(申请人提供)：该申请旨在发展候选人在哺乳动物遗传学方面的专业知识，并取得心血管疾病研究人员的独立地位。少数族裔候选人是迈阿密大学的一名非终身助理教授，在血管和分子生物学方面有扎实的培训和基础。候选人将获得杰出的机构支持，这项工作将在遗传学、生物信息学以及临床和基础血管生物学领域公认的领导者的指导下进行。目前跨学科项目的总体目标是利用最好的动物模型，通过从老鼠到人类(“正向遗传学”)的策略来表征支架内再狭窄(ISR)的遗传决定因素。利用近交系小鼠作为人类疾病的模型是合适的，因为两者都表现出易患常见的复杂血管疾病的倾向，如动脉粥样硬化和再狭窄；而且小鼠和人类的基因组密切相关，便于翻译。我们假设近交系小鼠之间支架内再狭窄的差异是由于遗传变异所致，这些多态基因可以通过小鼠全基因组关联和连锁定位来识别。我们将使用裸金属支架，并在至少22个遗传多样性的近交系菌株中监测多个相关的、被广泛接受的ISR端点，这些近交系菌株的基因类型在700多万个单核苷酸多态上公开可用。我们将确定具有不同表型的自交系中数量性状基因座的数量和位置，以表征对ISR的敏感性。我们将开发一个初步的全基因组单倍型关联图谱。在进一步的研究中，我们将确认和精细定位F2组合的连锁关系。在这里，我们将优先分析这些易感基因的候选基因，首先从那些与人类数据一致的基因开始，和/或根据已知的血管、炎症或增殖性疾病的功能。随着这些研究的成功完成，我们期望对ISR的遗传易感性提供公正的评估，这可能有助于基因候选识别、生物标记物的开发，并促进人类的类似研究。我们还希望为一系列竞争激烈的NIH拨款提供基础，这些拨款将把我们对遗传风险因素的发现扩展到发现高危个体的ISR药物靶点。相关性(参见说明书)：支架内再狭窄是5-25%的经皮冠状动脉介入治疗的主要并发症，这是疏通冠状动脉和促进冠状动脉血运重建的高效方法。识别支架内再狭窄的基因组危险因素是一项突破，为预防这些并发症和挽救生命提供了新的治疗策略和靶点。(摘要结束)

DESCRIPTION (provided by applicant): This application aims to develop the candidate's expertise in mammalian genetics and achieve independent status as an investigator in cardiovascular diseases. The minority candidate is a non-tenured Assistant Professor at the University of Miami with a solid training and foundation in vascular and molecular biology. The candidate will proceed with outstanding institutional support and the work will be performed under the mentorship of recognized leaders in genetics, bioinformatics, and clinical and basic vascular biology. The overall objective of the current inter-disciplinary project is to utilize the best-in-class animal model to characterize the genetic determinants of in-stent restenosis (ISR) using a mouse-to-human ('forward genetics) strategy. The use of inbred mice as a model for human disease is appropriate given both exhibit predispositions to common complex vascular disorders such as atherosclerosis and restenosis; and the mouse and human genomes are closely related facilitating translation. We hypothesize that differences in in- stent restenosis among inbred strains of mice are due to genetic variations and that these polymorphic genes can be identified through genome-wide association and linkage mapping in mice. We will use bare metal stents and monitor multiple relevant well-accepted ISR endpoints in at least 22 genetically diverse inbred strains whose genotypes are publicly available on over 7 million single nucleotide polymorphisms. We will determine the number and location of quantitative trait loci among inbred strains with different phenotypes that characterize susceptibility to ISR. We will develop a preliminary genome-wide haplotype association map. In further studies we will confirm and fine mapping linkage in F2 combined crosses. Herein, we will prioritize the analysis of candidate genes underlying these susceptibility loci by starting with those where concordance is demonstrated with human data, and/or on the basis of known function in vascular, inflammatory, or proliferative disorders. With the successful conclusion of these studies, we expect to provide an unbiased assessment of genetic susceptibility to ISR that may aid gene candidate identification, biomarker development, and facilitate similar studies in humans. We also expect to provide a foundation for a series of highly competitive NIH grants that will extend our findings of genetic risk factors to the discovery of drug targets for ISR in high-risk individuals. RELEVANCE (See instructions): In-stent restenosis is the major complication that occurs in 5-25% of cases of percutaneous coronary interventions, the highly effective way to unblock coronary arteries and facilitate coronary revascularization. Identifying the genomic risk factors for in stent restenosis represent a breakthrough that provides new therapeutic strategies and targets to prevent these complications and save lives. (End of Abstract)