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

基本信息

批准号：
8817328
负责人：
Christopher David Anderson
金额：
$ 18.62万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/8817328
关键词：
Accounting Address Affect Age-associated memory impairment Aging Alzheimer&apos 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 Genetic screening method Genomics Goals HDL-triglyceride Health 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 cerebral microbleeds combat computerized tools cost disorder prevention drug development drug discovery effective therapy genetic analysis genetic approach genetic variant genome-wide genome-wide analysis geriatric depression improved inhibitor/antagonist interdisciplinary approach low density lipoprotein triglyceride mortality neuroimaging next generation novel novel therapeutics patient population pleiotropism programs rare variant research and development skills therapeutic development tool treatment strategy

项目摘要

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）：克里斯托弗·D·安德森博士是马萨诸塞州综合医院（MGH）的神经关怀和中风神经科医生，其职业目标是开发一个独立的研究计划，作为一名计算遗传学家，能够使用先进的生物信息学和统计学方法，以利用较大的科学疾病，从而获得最大的科学率，从而提高了综合遗传和氏素质研究，并有意义地恢复了有意义的作用，并有意义地有意义地有意义地促进了有意义的作用。（CSVD）并确定治疗发育的新颖目标。作为实现这一目标的第一步，他计划使用来自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，以发现脂质影响CSVD的机制。该提案解决了争议的关键领域，因为当前的数据表明，根据研究的脑血管疾病的特定形式，脂质水平相互矛盾。脑部出血（ICH），放射线白质疾病和脑微粒的脑小血管疾病可能会因脂质水平降低而恶化，而整体缺血性中风风险似乎从该策略中受益。安德森（Anderson）博士在分析常见遗传变异数据中建立了早期的职业往绩，以识别缺血性中风，ICH和阿尔茨海默氏病的新关联，他的初步数据证明了生物知名的遗传分析在脑血管疾病中的可行性。他的职业计划利用了马萨诸塞州综合医院和广大研究所的广泛资源和特殊环境，在乔纳森·罗桑德（Jonathan Rosand）博士的指导下以及博士的同事。 Sekar Kathiresan，Mark Daly和Ona Wu。在这项职业发展奖中，安德森博士向以下方面提议：1）发现已知会影响脂质水平对CSVD的ICH风险的常见遗传变异和神经饰面表现的严重性的影响，2）2）2）2）确定稀有遗传变异在基因网络中的影响，在基因网络中具有质量和严重性的ICH和严重性的基因作用，以及3）的作用，以及3）与脂质水平相关的网络，并测试这些网络与ICH和神经影像措施相关的网络，以发现新的生物学靶标。拟议的研究将采用遗传和信息工具来证明脂质对CSVD的效果方向和幅度。这些分析提供了产生药物开发的新目标的希望，并将进一步了解脂质修饰治疗的潜在风险。安德森博士召集了一个在复杂疾病遗传学，脂质流行病学，神经影像学和先进的生物信息学技术方面具有专业知识的团队，该技术将确保该提案最大程度地利用生成的数据。该奖项将为安德森博士提供通过计算研究计划发展成为独立的临床医生的技能，该计划可以灵活地分析大型遗传数据集，以得出与他的临床患者人群预防和治疗脑血管疾病高度相关的结果。