RNA signatures of frontotemporal dementia and ALS due to C9ORF72 expansion

描述（由申请人提供）：这是加州大学弗朗西斯科记忆和衰老中心（MAC）神经遗传学研究员Jennifer Yokoyama博士的K 01奖申请。Yokoyama博士正在建立自己作为一个年轻的遗传学家进行神经退行性疾病的临床研究。K 01将为Yokoyama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测序的经验;（2）精通临床研究方法，包括在临床环境中解释遗传数据;（3）了解高级统计学;（4）发展独立的研究生涯。为了实现这些目标，Yokoyama博士组建了一个指导团队，其中包括两名主要导师：布鲁斯米勒博士（一位在神经退行性疾病方面具有专长的行为神经学家）和马修州立大学（Matthew State）（人类遗传学家和儿童精神病学家，具有基因发现方面的专业知识）;三位共同导师：霍华德罗森医生（神经学家，具有神经退行性疾病临床研究的专业知识），Kristine Yaffe（神经学家和精神病学家，具有流行病学/生物统计学方面的专业知识）和William塞利（神经学家，具有神经病理学方面的专业知识）;以及一位合作者：Giovanni Coppola博士（神经学家，具有人类遗传学和生物信息学方面的专业知识）。 拟议的研究项目侧重于由C9 ORF 72（C9+）重复扩增引起的神经退行性疾病，该疾病最近被确定为家族性额颞叶痴呆（FTD）和家族性肌萎缩侧索硬化症（ALS）的最常见原因。Yokoyama博士将开始通过研究C9+ FTD和C9+ ALS中外周基因表达与受影响脑组织的关系，阐明C9+可引起表型变异性（FTD与ALS）的生物学机制。目的1：Dr. Yokoyama将使用深度RNA测序确定外周RNA表达是否可区分C9+ FTD与C9+ ALS。目标二：Yokoyama博士将检测C9+ FTD和C9+ ALS患者中最易发生C9+病理的脑区的RNA表达是否因C9 ORF 72扩增长度而异。目标3：Yokoyama博士将进行探索性的全基因组关联研究，以确定驱动大脑区域特异性C9 ORF 72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剂和跟踪临床进展的生物标志物。这项研究具有创新性，因为它试图探索基因表达变化与局部脑病理学之间的关系，并将其与可能最终驱动临床疾病表现的新型遗传变异联系起来。拟议研究的结果将为我们理解C9 ORF 72扩增介导的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生物标志物。Yokoyama博士的K 01培训将使她准备使用复杂的神经解剖表型进行尖端的大脑疾病遗传研究。

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.