Relation of estrogen pathway genes to cognitive decline in elderly women and men

雌激素途径基因与老年女性和男性认知能力下降的关系

• 批准号: 8822075
• 负责人: Sarah Christine Janicki
• 金额: $ 13.23万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822075
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Amygdaloid structure; Applications Grants; Area; Blood Vessels; Brain; Brain imaging; CYP17A1 gene; CYP19A1 gene; Clinical; Cognitive; Communities; Cross-Sectional Studies; Data; Dementia; Development; Disease; ESR1 gene; ESR2 gene; Elderly; Elderly man; Elderly woman; Environment; Environmental Risk Factor; Estrogen Receptors; Estrogens; Ethnic Origin; Ethnic group; Fostering; Future; Gender; Gene Frequency; Genes; Genetic Polymorphism; Genetic Research; Genotype; Goals; Growth; Health; Height; Hippocampus (Brain); Hormonal; Hormone replacement therapy; Hormones; Image; Image Analysis; Impaired cognition; Individual; Intervention; Investigation; Learning; Life; Linkage Disequilibrium; Lobule; Magnetic Resonance Imaging; Measurement; Measures; Medial; Mediator of activation protein; Mentored Patient-Oriented Research Career Development Award; Mentorship; Methods; Mission; National Institute on Aging; Neurobiology; Outcome; Parietal; Pathology; Pathway interactions; Pattern; Population; Population Study; Race; Research; Risk; Risk Factors; Scientist; Single Nucleotide Polymorphism; Structure of inferior temporal gyrus; Structure of superior frontal gyrus; Structure of supramarginal gyrus; Supplementation; Techniques; Temporal Lobe; Testosterone; Thalamic structure; Thick; Training; Training Programs; Training and Education; Variant; Washington; White Matter Hyperintensity; Woman; Work; age related; angular gyrus; base; biological research; brain morphology; brain volume; career; cerebrovascular; cognitive change; cognitive testing; design; entorhinal cortex; genetic epidemiology; genetic variant; improved; men; multidisciplinary; neuroimaging; neuropathology; neuropsychological; public health relevance; socioeconomics; white matter change

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development Award (K23) will provide additional education and training for Dr. Sarah Janicki to establish herself as a clinical translational scientist in the hormonal mediators of cognitive decline and Alzheimer's disease (AD). An integrated multidisciplinary didactic and practical training program has been developed to allow Dr. Janicki to accomplish the following goals: 1) extend her training in advanced methods in the genetic epidemiology of aging; 2) learn and use longitudinal data analytic techniques; 3) develop expertise in neuromorphometric analytic techniques of structural MRI data; 4) transition to an independent career as a clinical translational scientist. Dr. Janicki's training program is supported by committed and enthusiastic mentorship from a panel of renowned experts in the genetics, epidemiology, cognitive assessment and neuroimaging of AD, and benefits from an outstanding intellectual environment, opportunities for career growth, and substantial institutional commitment. The objectives of the proposed research plan are to determine the contribution of estrogen biosynthetic pathway gene variants to cognitive decline, and to employ neuroimaging analyses to determine the underlying neurobiological pathways through which polymorphisms in these genes affect cognitive decline in elderly men and women of different ethnicities. Investigations in the neuropathology, neuroimaging, and neuropsychological studies of AD suggest that it is an estrogen-sensitive disease. Many prior studies evaluating the effect of estrogen on cognitive decline and brain morphology in the elderly have used study populations receiving exogenous estrogen supplementation, since age-related declines in endogenous hormones do not allow accurate assessment of estrogen status. However, hormone replacement therapy may have different effects on brain morphology than does lifelong hormone exposure due to composition and administration late in life. This study uses variants in genes of known estrogen receptor and biosynthetic function (ESR1, ESR2, CYP17, CYP19, and HSD17B1) as instrumental variables to estimate the effects of single nucleotide polymorphisms (SNPs) on changes in neuropsychological cognitive assessments and structural brain outcomes. The study population includes elderly men and women from the Washington Heights-Inwood Community Aging Project (WHICAP) and the Alzheimer's disease Neuroimaging Initiative (ADNI). Confirmatory analyses of significant findings will be performed in the Rotterdam Study (RS). Exploratory aims will examine how the effects of estrogen SNPs may vary by ethnicity due to socioeconomic and cerebrovascular risk factors associated with risk for cognitive decline. This study will lay the groundwork for future R01 grant applications identifying mechanisms of hormone action that direct areas of intervention in AD. This application directly supports the National Institute on Aging's proposed mission to conduct genetic and biological research related to diseases associated with aging, its objective to understand health differences and inequities associated with race, ethnicity, and gender among older adults, and its stated commitment to foster the development of clinician scientists in aging.

描述（由申请人提供）：这个指导以患者为导向的研究职业发展奖（K23）将为Sarah Janicki博士提供额外的教育和培训，以使自己成为认知衰退和阿尔茨海默病（AD）激素介导剂的临床转化科学家。Janicki博士完成了以下目标：1）扩展她在衰老遗传流行病学先进方法方面的培训; 2）学习和使用纵向数据分析技术; 3）发展结构MRI数据的神经形态学分析技术的专业知识; 4）过渡到独立的职业生涯作为临床转化科学家。Janicki博士的培训计划得到了遗传学，流行病学，认知评估和AD神经影像学领域知名专家小组的承诺和热情指导的支持，并受益于出色的智力环境，职业发展机会和实质性的机构承诺。拟议研究计划的目标是确定雌激素生物合成途径基因变异对认知能力下降的贡献，并采用神经影像学分析来确定这些基因多态性影响不同种族老年男性和女性认知能力下降的潜在神经生物学途径。调查 AD的神经病理学、神经影像学和神经心理学研究表明它是一种雌激素敏感性疾病。许多先前评估雌激素对老年人认知能力下降和脑形态学影响的研究使用了接受外源性雌激素补充的研究人群，因为与年龄相关的内源性激素下降无法准确评估雌激素状态。然而，激素替代疗法可能对脑形态产生不同的影响，而不是终身激素暴露，这是由于在生命后期的组合物和给药。本研究使用已知雌激素受体和生物合成功能（ESR 1，ESR 2，CYP 17，CYP 19和HSD 17 B1）的基因变体作为工具变量，以估计单核苷酸多态性（SNP）对神经心理学认知评估和结构性大脑结果变化的影响。研究人群包括来自华盛顿Heights-Inwood社区老龄化项目（WHICAP）和阿尔茨海默病神经影像学倡议（ADNI）的老年男性和女性。将在鹿特丹研究（RS）中对显著结果进行验证性分析。探索性的目的将检查雌激素SNP的影响如何因种族而异，这是由于与认知能力下降风险相关的社会经济和脑血管风险因素。这项研究将为未来的R 01拨款申请奠定基础，确定激素作用机制，指导AD干预领域。该应用程序直接支持国家老龄化研究所提出的使命，即进行与老龄化相关疾病的遗传和生物学研究，其目标是了解老年人中与种族，民族和性别相关的健康差异和不平等，以及其承诺促进临床科学家在老龄化方面的发展。