Genetics of In-Stent Restenosis: The Mouse to Human Strategy

描述（由申请人提供）：本申请旨在发展候选人在哺乳动物遗传学方面的专业知识，并作为心血管疾病研究者获得独立地位。少数族裔候选人是迈阿密大学的非终身助理教授，在血管和分子生物学方面有扎实的训练和基础。候选人将继续与优秀的机构支持和工作将在遗传学，生物信息学，临床和基础血管生物学公认的领导者的指导下进行。当前跨学科项目的总体目标是利用同类最佳动物模型，使用小鼠到人类（“正向遗传学”）策略来表征支架内再狭窄（ISR）的遗传决定因素。使用近交系小鼠作为人类疾病的模型是适当的，因为两者都表现出对常见的复杂血管疾病如动脉粥样硬化和再狭窄的易感性;并且小鼠和人类基因组密切相关，有助于翻译。我们假设近交系小鼠支架内再狭窄的差异是由于遗传变异，这些多态性基因可以通过小鼠全基因组关联和连锁图谱来识别。我们将使用裸金属支架，并监测至少22种遗传多样性近交系中多个相关的公认ISR终点，这些近交系的基因型在超过700万个单核苷酸多态性上是公开可用的。我们将确定数量和位置的数量性状基因座之间的近交系具有不同的表型，表征ISR的敏感性。我们将建立一个初步的全基因组单倍型关联图。在进一步的研究中，我们将确定和精细定位F2组合的连锁。在此，我们将优先分析这些易感基因座的候选基因，从那些与人类数据一致的基因开始，和/或基于血管、炎症或增殖性疾病中的已知功能。随着这些研究的成功结束，我们期望提供对ISR遗传易感性的无偏倚评估，这可能有助于候选基因的鉴定、生物标志物的开发，并促进人类的类似研究。我们还希望为一系列极具竞争力的NIH赠款提供基础，这些资助将我们对遗传风险因素的发现扩展到发现高危个体ISR的药物靶点。相关性（参见说明）：支架内再狭窄是发生在5-25%的经皮冠状动脉介入治疗病例中的主要并发症，经皮冠状动脉介入治疗是疏通冠状动脉和促进冠状动脉血运重建的高效方法。确定支架内再狭窄的基因组风险因素代表了一个突破，为预防这些并发症和挽救生命提供了新的治疗策略和目标。 (End摘要）

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)