Testosterone-Androgen Receptor Genetics: Role in Cognitive and Biological Aging

睾酮雄激素受体遗传学：在认知和生物衰老中的作用

• 批准号: 8912967
• 负责人: Matthew S Panizzon
• 金额: $ 11.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912967
• 关键词: Accounting; Adult; Affect; Age; Aging; Alzheimer' s Disease; Androgen Receptor; Androgens; Animals; Award; Baltimore; Binding; Bioinformatics; Biological Aging; Brain; CAG repeat; California; Cardiovascular Diseases; Cognition; Cognitive; Cognitive aging; DNA; Data; Development; Discipline; Disease; Endocrine; Exons; Faculty; Genes; Genetic; Genetic Determinism; Genetic study; Genotype; Goals; Health; Hormones; Human; Individual; K-Series Research Career Programs; Knowledge; Lead; Learning; Length; Light; Longitudinal Studies; Mental Depression; Metabolic syndrome; Methods; Molecular Genetics; Neurocognitive; Neuroendocrinology; Obesity; Onset of illness; Other Genetics; Outcome; Pathway interactions; Phenotype; Physical Function; Physiological; Positioning Attribute; Process; Psychiatry; Receptor Gene; Research; Research Personnel; Resources; Role; Sampling; Staging; Structure; System; Testing; Testosterone; Therapeutic Intervention; Time; Training; Training Programs; Transcription Coactivator; Translating; Twin Multiple Birth; Twin Studies; Universities; Variant; Vietnam; age related; aging brain; career development; cognitive function; experience; follow-up; frailty; functional decline; gene interaction; hormone therapy; improved; innovation; male; men; middle age; mild cognitive impairment; multidisciplinary; neuroimaging; normal aging; older men; personalized medicine; physical conditioning; programs; receptor; receptor function

DESCRIPTION (provided by applicant): The purpose of this career development award is to assist me in gaining the knowledge and experience necessary to become a successful, independent investigator in multidisciplinary aging research. Over the course of the four year award period I will obtain formal training in the development of an integrative aging research program (Training Goal 1), as well as learn the principles and methods of two disciplines that I believe are critical to studying the genetics of cognitive and biological aging: molecular genetics (Training Goal 2) and neuroendocrinology (Training Goal 3). The Department of Psychiatry at the University of California San Diego is an ideal setting for this project, because it possesses several well-established aging research programs, a world-class faculty, and numerous state-of-the-field scientific resources. It is fully committed to my career development. As a clinically trained neuropsychologist with experience in the use of the twin method to study neurocognitive phenotypes, I am uniquely positioned to benefit from this additional training, and in doing so accomplish my goal of developing an integrative cognitive and brain aging research program. The scientific component of this proposal will examine the genetic factors that regulate the relationships among testosterone (T) and aging-related changes in cognition, brain, and health. T declines with increasing age, and has been associated with multiple cognitive, brain, and health-related aging phenotypes. I hypothesize that the effects of T differ as a function of the number of trinucleotide (CAG) repeats in the androgen receptor (AR) gene. There is a critical knowledge gap in understanding the impact of this variation in the AR gene and other T-related genes on the relationships among T, cognition, brain, and health. With data from two genetically informative samples with similar cognitive, neuroimaging, health, and endocrine data (the Vietnam Era Twin Study of Aging and the Baltimore Longitudinal Study of Aging) I will be able to fill this knowledge gap. The specific aims are: 1) Characterize how variation in the AR gene influences androgen- and age-sensitive phenotypes; 2) Elucidate the extent to which variation in the AR gene affects other genetic determinants of androgen- and age-sensitive phenotypes; and 3) Determine whether T and variation in the AR gene predict changes in cognition, brain, and health over time. Innovative aspects of this proposal are that it sets the stage for a genetically informed, personalized medicine approach to treating T deficiency by focusing on the T-AR gene interaction; it translates and extends findings from primarily animal studies into humans; and it examines aging-related changes beginning in mid-life, prior to the onset of disease, rather than in old age. Relevance: By elucidating the genetic factors that regulate the relationships among testosterone (T), cognition, brain, and health in aging men, this study will shed new light on the function of T, as well as identify individuals most susceptible to age-related changes in T and most likely to benefit from hormone therapy.

描述（由申请人提供）：这个职业发展奖项的目的是帮助我获得必要的知识和经验，成为一个成功的，独立的研究者在多学科老龄化研究。在为期四年的奖励期内，我将获得关于综合衰老研究项目发展的正式培训（培训目标1），并学习我认为对研究认知和生物衰老的遗传学至关重要的两个学科的原理和方法：分子遗传学