RNA signatures of frontotemporal dementia and ALS due to C9ORF72 expansion

描述（由申请人提供）：这是Jennifer Yokoyama博士的K01奖申请，她是加州大学旧金山记忆与衰老中心（MAC）的神经遗传学研究员。横山博士正在成为一名从事神经退行性疾病临床研究的年轻遗传学家。该K01将为横山博士提供必要的支持，以实现以下目标：(1)获得使用下一代转录组学测序的经验；(2)熟练掌握临床研究方法，包括在临床环境中解释遗传数据；（三）了解高级统计学；(4)发展独立的研究事业。为了实现这些目标，横山博士组建了一个指导团队，其中包括两位主要导师：Bruce Miller（神经退行性疾病方面的行为神经学家）和Matthew State（基因发现方面的人类遗传学家和儿童精神病学家）；三位共同导师：博士；Howard Rosen（专攻神经退行性疾病临床研究的神经学家），Kristine Yaffe（专攻流行病学/生物统计学的神经学家和精神病学家）和William Seeley（专攻神经病理学的神经学家）；还有一位合作者乔瓦尼·科波拉（Giovanni Coppola）博士（一位专攻人类遗传学和生物信息学的神经学家）。拟议的研究项目重点关注由C9ORF72 （C9+）重复扩增引起的神经退行性疾病，该基因最近被确定为家族性额颞叶痴呆（FTD）和家族性肌萎缩性侧索硬化症（ALS）的最常见原因。横山博士将通过研究C9+ FTD和C9+ ALS中外周基因表达与受影响脑组织的关系，开始阐明C9+引起表型变异（FTD与ALS）的生物学机制。目的1：横山博士将使用深度RNA测序确定外周RNA表达是否能区分C9+ FTD和C9+ ALS。目的2：横山博士将测试在C9+ FTD和C9+ ALS患者中，最易受C9+病理影响的大脑区域的RNA表达是否会根据C9ORF72扩增长度而变化。目标3：横山博士将进行探索性全基因组关联研究，以确定驱动大脑区域特异性C9ORF72扩增和临床综合征的遗传变异。该项目的最终目标是确定可用于筛选疾病修饰因子和跟踪临床进展的生物标志物。拟议的研究具有创新性，因为它试图探索基因表达变化与局部脑病理之间的关系，并将这些变化与可能最终驱动临床疾病表现的新型遗传变异联系起来。拟议研究的结果将对我们理解C9ORF72扩增介导疾病的生物学机制做出重大贡献，并确定可能导致新疗法的信息性生物标志物。横山博士的K01培训将为她利用复杂的神经解剖表型进行尖端的脑部疾病遗传研究做好准备。

DESCRIPTION (provided by applicant): This is an application for a K01 award for Dr. Jennifer Yokoyama, a neurogenetics fellow at the University of California, San Francisco Memory and Aging Center (MAC). Dr. Yokoyama is establishing herself as a young geneticist conducting clinical research on neurodegenerative disease. This K01 will provide Dr. Yokoyama with the support necessary to accomplish the following goals: (1) to gain experience in the use of next-generation sequencing for transcriptomics; (2) to become proficient in clinical research methodologies, including interpretation of genetic data in clinical settings; (3) to obtain an understanding of advanced statistics; and (4) to develop an independent research career. To achieve these goals, Dr. Yokoyama has assembled a mentoring team including two primary mentors: Drs. Bruce Miller (a behavioral neurologist with expertise in neurodegenerative disease) and Matthew State (a human geneticist and child psychiatrist with expertise in gene discovery); three co-mentors: Drs. Howard Rosen (a neurologist with expertise in clinical research in neurodegenerative disease), Kristine Yaffe (a neurologist and psychiatrist with expertise in epidemiology/biostatistics), and William Seeley (a neurologist with expertise in neuropathology); and one collaborator: Dr. Giovanni Coppola (a neurologist with expertise in human genetics and bioinformatics). The proposed research project focuses on neurodegenerative diseases caused by repeat expansion of C9ORF72 (C9+), which was recently identified as the most common cause of both familial frontotemporal dementia (FTD) and familial amyotrophic lateral sclerosis (ALS). Dr. Yokoyama will begin to elucidate the biological mechanism by which C9+ can cause phenotypic variability (FTD versus ALS) by studying the relationship of peripheral gene expression to affected brain tissue in C9+ FTD and C9+ ALS. Aim 1: Dr. Yokoyama will determine whether peripheral RNA expression differentiates C9+ FTD from C9+ ALS using deep RNA sequencing. Aim 2: Dr. Yokoyama will test whether RNA expression in brain regions most vulnerable to C9+ pathology varies based on C9ORF72 expansion length in C9+ FTD and C9+ ALS patients. Aim 3: Dr. Yokoyama will perform exploratory genome-wide association studies to identify genetic variation that drives brain region-specific C9ORF72 expansion and clinical syndrome. The ultimate goal of this project is to identify biomarkers that can be used to screen for modifiers of disease and track clinical progression. The proposed research is innovative because it seeks to explore the relationship between changes in gene expression and local brain pathology, and to link these to novel genetic variation that may ultimately drive clinical disease presentation. Results from the proposed research will make significant contributions to our understanding of biological mechanisms underlying C9ORF72 expansion-mediated disease and identify informative biomarkers that could lead to novel therapies. Dr. Yokoyama's K01 training will prepare her to conduct cutting edge genetic studies of brain disorders using sophisticated neuroanatomical phenotypes.