Genetic and Epigenetic Factors of Age-Related Cognitive Decline - A Twin Study

描述（由申请人提供）：Brinda K. Rana博士是加州大学圣地亚哥分校（UCSD）医学院精神病学系的助理教授，她正在与主要导师William Kremen博士和共同导师Nicholas Schork博士一起申请K 01指导研究科学家发展奖。拟议的K 01培训的目标是获得以下方面的培训：（1）认知老化研究;（2）研究设计;和（3）表观遗传学。这次培训将使Rana博士能够实现她在认知衰老基因组学领域的独立研究员的职业目标。培训目标将通过以下方式实现：开展拟议的研究，参加Kremen博士实验室正在进行的认知评估，与合作者Michael里昂和林登Eaves进行双胞胎方法学培训，以及参加Stein老龄化研究所的讲习班、课程和研讨会。Rana博士的主要导师是Kremen博士，他是UCSD神经精神评估和衰老研究的专家，也是越南时代双胞胎衰老研究（VETSA）的主要研究者。Rana博士的共同导师Schork博士是加利福尼亚州拉霍亚斯克里普斯研究所的统计遗传学家，他正在开发DNA甲基化方法。林登伊夫斯博士、迈克尔里昂博士和迈克尔尼尔博士是这个项目的合作者，他们将指导拉纳博士的孪生方法。加州大学圣地亚哥分校生物工程系的张昆博士是全基因组DNA甲基化技术的专家，他将担任DNA甲基化研究的现场顾问。Shah Golshan博士将担任大量基因组数据库的顾问。拟议研究的总体目标是“与年龄相关的认知衰退的遗传和表观遗传因素-双胞胎研究”，通过表观遗传研究更好地了解与年龄相关的神经认知变化的基因组和环境预测因素。具体而言，来自VETSA队列的DNA样本和纵向表型数据将用于实现这一目标。VETSA是一项正在进行的纵向研究，专门用于调查随着时间的推移认知过程的遗传和环境因素，其特殊功能包括对1200多对双胞胎进行双胞胎采样，可以估计表型的遗传性，每个人的详细认知和相关表型数据，生化表型，如皮质醇水平，以及一些认知和生化表型的纵向数据。此外，表型数据从中年开始，这允许识别健康认知老化的预测因子。将使用经典双胞胎设计、共双胞胎对照设计和非双胞胎设计的组合来确定DNA甲基化在认知和脑老化中的作用。 公共卫生相关性：随着美国和其他地区老年人口的增加，确定导致与年龄相关的神经认知下降和恢复力下降的遗传和后天因素正在成为优先事项。我建议应用双胞胎的方法学在一个独特的队列的主题收集通过越南时代的双胞胎研究老化，以确定表观遗传因素。本研究的总体目标是通过DNA甲基化研究更好地了解与年龄相关的神经认知变化的基因组和环境预测因子。

DESCRIPTION (provided by applicant): Brinda K. Rana, PhD, an Assistant Professor in the Department of Psychiatry at the University of California, San Diego (UCSD) School of Medicine, is applying for the K01 Mentored Research Scientist Development Award with primary mentor Dr. William Kremen and co-mentor Dr. Nicholas Schork. The goals of the proposed K01 training are to obtain training in (1) cognitive aging research; (2) research design; and (3) epigenetics. This training will enable Dr. Rana to reach her career goal of an independent researcher in the field of genomics of cognitive aging. The training objectives will be met through a combination of conducting the proposed research, participating in on-going cognitive assessments in Dr. Kremen's laboratory, visits with collaborators Michael Lyons and Lindon Eaves for training in twin methodology, and participation in workshops, courses, and seminars at the Stein Institute for Research in Aging. Dr. Rana's primary mentor is Dr. Kremen, an expert in neuropsychiatric assessments and aging research at UCSD and Principle Investigator on the Vietnam Era Twin Study of Aging (VETSA). Dr. Rana's co-mentor, Dr. Schork, a statistical geneticist at The Scripps Research Institute in La Jolla, CA who is developing DNA methylation methodologies. Drs. Lindon Eaves, Michael Lyons, and Michael Neale are collaborators on this project and will mentor Dr. Rana in twin methodology. Dr. Kun Zhang in the UCSD Department of Bioengineering is an expert in whole genome DNA methylation technologies, and will serve as an on-site consultant for DNA methylation studies. Dr. Shah Golshan will serve as a consultant for databasing large amounts of genomic data. The overall goal of the proposed research, "Genetic and Epigenetic Factors of Age-Related Cognitive Decline-A Twin Study," is to better understand genomic and environmental predictors of age-related neurocognitive changes through epigenetic studies. Specifically, the DNA samples and longitudinal phenotype data from the VETSA cohort will be used to address this goal. VETSA is an ongoing longitudinal study specifically designed to investigate the genetic and environmental contributors to cognitive processes over time with special features that include twin sampling of over 1200 twins that enables the estimation of heritability of phenotypes, detailed cognitive and related phenotype data on each individual, biochemical phenotypes such as cortisol levels, and longitudinal data on some cognitive and biochemical phenotypes. In addition, the phenotype data starts at midlife which allows for the identification of predictors of healthy cognitive aging. A combination of classical twin design, co-twin control design, and non-twin design will be used to determine the role of DNA methylation in cognitive and brain aging. PUBLIC HEALTH RELEVANCE: With the increasing population of aged individuals in the United States and outside, identifying inherited and acquired factors contributing to age-related neurocognitive decline and resilience from decline is becoming a priority. I propose to apply twin methodology on a unique cohort of subjects collected through the Vietnam Era Twin Study of Aging to identify epigenetic factors. The overall goal of this study is to better understand genomic and environmental predictors of age-related neurocognitive changes through DNA methylation studies.