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

描述(由申请者提供)：这个有指导的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，以确立她作为认知衰退和阿尔茨海默病(AD)荷尔蒙调节剂的临床翻译科学家的地位。为了实现以下目标，Janicki博士开发了一个综合性的多学科教学和实践培训计划：1)扩展她在衰老遗传流行病学方面的高级方法方面的培训；2)学习和使用纵向数据分析技术；3)发展结构磁共振数据的神经形态计量分析技术方面的专业知识；4)过渡到独立的临床翻译科学家职业生涯。Janicki博士的培训计划得到了遗传学、流行病学、认知评估和阿尔茨海默病神经成像方面知名专家小组的坚定和热情的指导，并受益于出色的智力环境、职业发展机会和重大的机构承诺。该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功能下降的贡献，并利用神经成像分析来确定这些基因的多态通过哪些潜在的神经生物学途径影响不同种族的老年男性和女性的认知功能下降。在中国的调查 AD的神经病理学、神经影像和神经心理学研究表明，它是一种雌激素敏感型疾病。许多先前评估雌激素对老年人认知衰退和脑形态的影响的研究都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，激素替代疗法可能会对大脑形态产生不同于终身激素暴露的影响，这是因为激素的成分和晚年给药。本研究使用已知的雌激素受体和生物合成功能基因(ESR1、ESR2、CyP17、CyP19和HSD17B1)的变异作为工具变量，以评估单核苷酸多态(SNPs)对神经心理认知评估和结构性脑结果的影响。研究人群包括来自华盛顿高地-因伍德社区老龄化项目(WHICAP)和阿尔茨海默病神经成像倡议(ADNI)的老年男性和女性。鹿特丹研究(RS)将对重大发现进行验证性分析。探索性目标将研究雌激素SNPs的影响如何因种族而变化，因为社会经济和脑血管风险因素与认知能力下降的风险相关。这项研究将为将来的R01拨款申请奠定基础，确定指导AD干预领域的激素作用机制。这一应用程序直接支持国家老龄研究所的拟议使命，即进行与衰老相关的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，以及其声明的促进老龄临床医生科学家发展的承诺。

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.