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

支架内再狭窄的遗传学：从小鼠到人类的策略

• 批准号: 7923378
• 负责人: Roberto Irenardo Vazquez Padron
• 金额: $ 10.68万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923378
• 关键词: Animal Model; Atherosclerosis; Bioinformatics; Biological Markers; Biology; Blood Vessels; Candidate Disease Gene; Cardiovascular Diseases; Chromosome Mapping; Clinical; Complex; Complication; Coronary; Coronary artery; Data; Development; Disease; Drug Delivery Systems; Exhibits; Foundations; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Grant; Haplotypes; Homologous Gene; Human; Human Genome; Inbred Mouse; Inbred Strain; Inbred Strains Mice; Individual; Inflammatory; Instruction; Life; Location; Mammalian Genetics; Maps; Mentorship; Metals; Minority; Modeling; Molecular Biology; Monitor; Mus; Pattern; Phenotype; Predisposition; Quantitative Trait Loci; Research; Research Personnel; Risk Factors; Series; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Solid; Stents; Susceptibility Gene; Training; Translations; United States National Institutes of Health; Universities; Vascular Diseases; Work; abstracting; base; candidate identification; genetic analysis; genetic risk factor; genome wide association study; genome-wide; high risk; human data; human disease; mouse model; novel; novel therapeutics; percutaneous coronary intervention; prevent; professor; restenosis

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)

描述（由申请人提供）：本申请旨在培养候选人在哺乳动物遗传学方面的专业知识，并获得心血管疾病研究人员的独立地位。少数派候选人是迈阿密大学的非终身教授助理教授，在血管和分子生物学方面拥有扎实的训练和基础。候选人将在出色的机构支持下继续进行，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。当前跨学科项目的总体目标是利用同类最佳的动物模型，通过小鼠到人类（“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模型是合适的，因为它们都表现出对常见复杂血管疾病（如动脉粥样硬化和再狭窄）的倾向；小鼠和人类基因组密切相关，有利于翻译。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造成的，并且这些多态性基因可以通过小鼠的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 个遗传多样性近交系的多个相关的公认 ISR 终点，这些近交系的基因型已公开，超过 700 万个单核苷酸多态性。我们将确定具有不同表型的近交系中数量性状基因座的数量和位置，这些表型表征了对 ISR 的易感性。我们将开发一个初步的全基因组单倍型关联图。在进一步的研究中，我们将确认和精细定位 F2 组合杂交中的连锁。在此，我们将优先分析这些易感位点背后的候选基因，从那些与人类数据证明一致的基因开始，和/或基于血管、炎症或增殖性疾病中已知的功能。随着这些研究的成功结束，我们期望对 ISR 的遗传易感性提供公正的评估，这可能有助于候选基因的识别、生物标志物的开发，并促进人类的类似研究。我们还期望为一系列竞争激烈的 NIH 拨款奠定基础，将我们对遗传风险因素的发现扩展到高风险个体 ISR 药物靶点的发现。相关性（参见说明）：支架内再狭窄是 5-25% 经皮冠状动脉介入治疗病例中发生的主要并发症，这是疏通冠状动脉并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危险因素代表了一项突破，为预防这些并发症和拯救生命提供了新的治疗策略和目标。 （摘要完）