Genetic Analyses of Lipids in Cerebral Hemorrhage and Small Vessel Disease

描述(申请人提供)：Christopher D.Anderson博士是马萨诸塞州综合医院(MGH)的神经危重护理和卒中神经科医生，他的职业目标是开发一个独立的研究计划，作为一名计算遗传生物学家，能够使用先进的生物信息学和统计学方法从大规模的遗传和基因组研究中获得最大的科学成果，目的是返回有意义和可操作的结果，以提高对脑部小血管疾病(CSVD)的了解，并确定治疗开发的新靶点。作为实现这一目标的第一步，他计划使用全基因组研究的数据来检查与血脂水平相关的生物网络中的遗传变异，以揭示血脂影响CSVD的机制。这项建议解决了一个关键的争议领域，因为目前的数据表明，根据正在研究的特定形式的脑血管疾病，血脂水平的作用存在冲突。脑小血管疾病是脑出血(ICH)、放射性脑白质疾病和脑微出血的基础，降低血脂水平可能会加重脑部小血管疾病，而整体缺血性中风风险似乎从这一策略中受益。安德森博士在分析常见的基因变异数据以确定缺血性中风、脑出血和阿尔茨海默病的新关联方面建立了早期的职业记录，他的初步数据证明了在脑血管疾病中进行生物知情基因分析的可行性。他的职业规划利用了马萨诸塞州综合医院和博德研究所的广泛资源和特殊环境，在Jonathan Rosand博士的指导下，以及Sekar Kathiresan、Mark Daly和Ona Wu博士的共同指导下。在这项职业发展奖中，安德森博士建议：1)发现已知影响血脂水平的常见基因变异对脑出血风险和CSVD神经成像表现的严重程度的影响；2)确定与血脂水平有关的基因网络中罕见的基因变异对脑出血风险和这些同样的神经成像指标的严重程度的影响；3)使用先进的生物信息学工具构建与血脂水平相关的新基因网络，并测试这些网络与脑出血和神经成像措施的关联，以发现新的生物靶点。这项拟议的研究将使用遗传学和信息学工具来证明脂类对CSVD的影响的方向和程度。这些分析为药物开发提供了新的靶点，并将进一步加深我们对脂质调节治疗的潜在风险的理解。安德森博士组建了一支在复杂疾病遗传学、血脂流行病学、神经成像和先进生物信息学技术方面拥有专业知识的团队，以确保该提案最大限度地利用所产生的数据。这一奖项将为安德森博士提供技能，使他能够发展成为一名独立的临床科学家和计算机研究计划，该计划可以灵活地分析大型基因数据集，以得出与他的临床患者群体的脑血管疾病预防和治疗高度相关的结果。

DESCRIPTION (provided by applicant): Dr. Christopher D. Anderson is a Neurocritical Care and Stroke Neurologist at Massachusetts General Hospital (MGH), whose career goal is to develop an independent research program as a computational genetic biologist capable of using advanced bioinformatic and statistical methods to obtain maximal scientific yield from large-scale genetic and genomic studies, with the aim of returning meaningful and actionable results that improve understanding of cerebral small vessel disease (CSVD) and identify novel targets for therapeutic development. As a first step toward this goal, he plans to use data from genome-wide studies to examine genetic variants within biological networks associated with lipid levels to uncover the mechanisms by which lipids influence CSVD. This proposal addresses a key area of controversy, as current data suggest conflicting roles for lipid levels depending on the particular form of cerebrovascular disease under study. Cerebral small vessel disease, which underlies intracerebral hemorrhage (ICH), radiographic white matter disease, and cerebral microbleeds, may be worsened by reduced lipid levels, while overall ischemic stroke risk appears to benefit from this strategy. Dr. Anderson has established an early career track record in the analysis of common genetic variant data to identify new associations in ischemic stroke, ICH, and Alzheimer Disease, and his preliminary data demonstrate the feasibility of biologically-informed genetic analysis in cerebrovascular disease. His career plan leverages the extensive resources and exceptional environments of Massachusetts General Hospital and the Broad Institute, under the mentorship of Dr. Jonathan Rosand and co-mentorship of Drs. Sekar Kathiresan, Mark Daly, and Ona Wu. In this Career Development Award, Dr. Anderson proposes to: 1) discover the impact of common genetic variants known to affect lipid levels on the risk of ICH and severity of neuroimaging manifestations of CSVD, 2) determine the impact of rare genetic variants in gene networks with a role in lipid levels on risk of ICH and severity of these same neuroimaging measures, and 3) use advanced bioinformatics tools to construct novel gene networks associated with lipid levels, and test these networks for association with ICH and neuroimaging measures to uncover new biological targets. The proposed study will employ genetic and informatic tools to demonstrate the direction and magnitude of effect that lipids exert on CSVD. These analyses offer the promise of yielding novel targets for drug development, and will further our understanding of the potential risks of lipid modifying therapy. Dr. Anderson has assembled a team with expertise in complex disease genetics, lipid epidemiology, neuroimaging, and advanced bioinformatics techniques that will ensure that this proposal maximally leverages the data generated. This Award will provide Dr. Anderson with the skills to evolve into an independent clinician-scientist with a computational research program that can nimbly analyze large genetic datasets to derive results that are highly relevant to the prevention and treatment of cerebrovascular disease in his clinical patient population.