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）：该职业发展奖的目的是帮助我获得成为多学科衰老研究领域成功的独立研究者所需的知识和经验。在四年的奖励期内，我将获得开发综合衰老研究计划（培训目标 1）的正式培训，并学习我认为对研究认知和生物衰老遗传学至关重要的两个学科的原理和方法：分子遗传学 （培训目标 2）和神经内分泌学（培训目标 3）。加州大学圣地亚哥分校精神病学系是该项目的理想场所，因为它拥有多个完善的老龄化研究项目、世界一流的师资队伍和众多前沿的科学资源。它完全致力于我的职业发展。作为一名经过临床训练的神经心理学家，拥有使用双胞胎方法研究神经认知表型的经验，我处于独特的位置，可以从这种额外的培训中受益，并通过这样做实现我开发综合认知和大脑老化研究计划的目标。 该提案的科学部分将研究调节睾酮 (T) 与衰老相关的认知、大脑和健康变化之间关系的遗传因素。 T 随着年龄的增长而下降，并且与多种认知、大脑和健康相关的衰老表型有关。我假设 T 的影响随雄激素受体 (AR) 基因中三核苷酸 (CAG) 重复次数的变化而变化。在理解 AR 基因和其他 T 相关基因的这种变异对 T、认知、大脑和健康之间关系的影响方面存在着关键的知识差距。借助两个具有相似认知、神经影像、健康和内分泌数据的遗传信息样本（越南时代双胞胎衰老研究和巴尔的摩纵向衰老研究）的数据，我将能够填补这一知识空白。具体目标是： 1) 描述 AR 基因的变异如何影响雄激素和年龄敏感表型； 2) 阐明AR基因变异对雄激素和年龄敏感表型的其他遗传决定因素的影响程度； 3) 确定 AR 基因中的 T 和变异是否可以预测认知、大脑和健康状况随时间的变化。该提案的创新之处在于，它为通过关注 T-AR 基因相互作用来治疗 T 缺乏症的遗传信息、个性化医学方法奠定了基础；它将主要动物研究的发现转化并扩展到人类；它检查中年时期疾病发作之前而不是老年时开始的与衰老相关的变化。相关性：通过阐明调节老年男性睾酮 (T)、认知、大脑和健康之间关系的遗传因素，这项研究将为 T 的功能提供新的认识，并确定最容易受到与年龄相关的 T 变化的影响，并且最有可能从激素治疗中受益的个体。