Genetic Analyses of Lipids in Cerebral Hemorrhage and Small Vessel Disease

脑出血和小血管疾病中脂质的遗传分析

• 批准号: 8677019
• 负责人: Christopher David Anderson
• 金额: $ 19.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677019
• 关键词: Accounting; Address; Affect; Age-associated memory impairment; Aging; Alzheimer' s Disease; Area; Award; Bioinformatics; Biological; Biology; Caring; Cerebral hemisphere hemorrhage; Cerebrovascular Disorders; Cerebrum; Cholesterol; Cholesterol Ester Transfer Proteins; Clinical; Clinical Trials; Clinical/Radiologic; Complex; Computational Biology; Computational Technique; Conflict (Psychology); Data; Data Set; Development; Development Plans; Disease; Ensure; Environment; Epidemiologic Methods; Epidemiology; Functional disorder; Gait; Gait abnormality; General Hospitals; Genes; Genetic; Genetic Determinism; Genetic Risk; Genetic Techniques; Genetic Variation; Genomics; Goals; HDL-triglyceride; Hereditary Disease; High Density Lipoproteins; Individual; Informatics; Institutes; International; Ischemic Stroke; K-Series Research Career Programs; Lipids; Low-Density Lipoproteins; Massachusetts; Measures; Mediating; Medical; Mentorship; Microvascular Dysfunction; Neurologist; Pathogenesis; Pharmaceutical Preparations; Phenotype; Play; Population; Prevention; Prevention strategy; Research; Resources; Risk; Role; Scientist; Severities; Statistical Methods; Stroke; Stroke prevention; Techniques; Testing; Training; Triglycerides; Variant; Vascular Cognitive Impairment; White Matter Disease; White Matter Hyperintensity; age related; career; career development; case control; combat; computerized tools; cost; disorder prevention; drug development; drug discovery; effective therapy; genetic analysis; genetic variant; genome wide association study; genome-wide; geriatric depression; improved; inhibitor/antagonist; interdisciplinary approach; low density lipoprotein triglyceride; mortality; neuroimaging; next generation; novel; novel therapeutics; patient population; programs; public health relevance; rare variant; research and development; skills; therapeutic development; tool; treatment strategy

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.

描述（由申请人提供）：Christopher D.安德森是马萨诸塞州总医院（MGH）的神经重症监护和中风神经学家，其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方法，从大规模的遗传和基因组研究中获得最大的科学收益，目的是返回有意义和可操作的结果，提高对脑小血管疾病（CSVD）的理解，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脂质水平相关的生物网络中的遗传变异，以揭示脂质影响CSVD的机制。这一建议解决了一个关键的争议领域，因为目前的数据表明，根据所研究的脑血管疾病的特定形式，血脂水平的作用相互矛盾。脑小血管疾病是脑内出血（ICH）、放射学白色病变和脑微出血的基础，可能因血脂水平降低而恶化，而总体缺血性卒中风险似乎从该策略中获益。安德森博士在分析常见遗传变异数据以确定缺血性卒中、ICH和阿尔茨海默病的新关联方面建立了早期职业记录，他的初步数据证明了脑血管疾病生物学信息遗传分析的可行性。他的职业规划利用了马萨诸塞州总医院和布罗德研究所的广泛资源和特殊环境，在Jonathan Rosand博士的指导下，并由Sekar Kathiresan博士、Mark Daly博士和Ona Wu博士共同指导。在这个职业发展奖中，安德森博士建议：1）发现已知影响脂质水平的常见遗传变异对ICH风险和CSVD神经影像学表现严重程度的影响，2）确定在脂质水平中起作用的基因网络中罕见遗传变异对ICH风险和这些相同神经影像学指标严重程度的影响，3）利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，并检测这些网络与脑出血和神经影像学指标的相关性，以发现新的生物学靶点。 这项拟议的研究将采用遗传和信息学工具来证明脂质对CSVD的影响方向和程度。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调脂治疗潜在风险的理解。安德森博士组建了一个拥有复杂疾病遗传学、脂质流行病学、神经影像学和先进生物信息学技术专业知识的团队，以确保该提案最大限度地利用所产生的数据。该奖项将为安德森博士提供技能，使其发展成为一名独立的临床科学家，拥有一个计算研究程序，可以灵活地分析大型遗传数据集，以获得与其临床患者人群中脑血管疾病的预防和治疗高度相关的结果。