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

描述(申请人提供)：这个职业发展奖的目的是帮助我获得必要的知识和经验，成为一名成功的，在多学科老龄化研究的独立调查员。在四年的获奖期内，我将接受关于发展综合衰老研究计划(培训目标1)的正式培训，并学习两个学科的原理和方法，我认为这两个学科对研究认知和生物衰老的遗传学至关重要：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的精神病学系是这个项目的理想场所，因为它拥有几个成熟的老龄研究项目，世界级的教师队伍，以及众多最先进的科学资源。它完全致力于我的职业发展。作为一名受过临床培训的神经心理学家，在使用TWIN方法研究神经认知表型方面有经验，我处于独特的地位，可以从这种额外的培训中受益，并通过这样做来实现我的目标，即开发一个综合认知和大脑老化研究计划。该提案的科学部分将研究调节睾酮(T)与认知、大脑和健康方面与衰老相关的变化之间关系的遗传因素。T随着年龄的增长而下降，并与多种认知、大脑和健康相关的衰老表型有关。我假设T的作用随着雄激素受体(AR)基因中三核苷酸(CAG)重复次数的不同而不同。在理解AR基因和其他T相关基因的这种变异对T、认知、大脑和健康之间的关系的影响方面，有一个关键的知识缺口。有了来自两个具有相似认知、神经成像、健康和内分泌数据的遗传信息样本的数据(越南时代双胞胎老龄化研究和巴尔的摩老龄化纵向研究)，我将能够填补这一知识空白。其具体目的是：1)确定AR基因的变异如何影响雄激素和年龄敏感的表型；2)阐明AR基因的变异对雄激素和年龄敏感的表型的其他遗传决定因素的影响程度；3)确定T和AR基因的变异是否预测随着时间的推移认知、大脑和健康的变化。这项提案的创新方面是，它通过关注T-AR基因的相互作用，为通过遗传信息和个性化医学方法治疗T缺乏症奠定了基础；它将主要来自动物的研究结果转化并扩展到人类；它检查了从中年开始，即疾病发作之前，而不是老年时与衰老相关的变化。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的功能提供新的线索，并确定最容易受到与年龄相关的T变化的个体，以及最有可能从激素治疗中受益的个体。

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.