RNA signatures of frontotemporal dementia and ALS due to C9ORF72 expansion

C9ORF72 扩增导致额颞叶痴呆和 ALS 的 RNA 特征

基本信息

批准号：
8805219
负责人：
Jennifer S Yokoyama
金额：
$ 12.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8805219
关键词：
Address Affect Aging Amyotrophic Lateral Sclerosis Behavioral Bioinformatics Biological Biological Markers Biological Models Biometry Brain Brain Diseases Brain Pathology Brain region C9ORF72 California Child Clinical Clinical Data Clinical Research Collaborations Data Development Disease Epidemiology Familial Amyotrophic Lateral Sclerosis Fostering Frontotemporal Dementia Future Gene Expression Genes Genetic Genetic Research Genetic Risk Genetic Transcription Genetic Variation Genetic study Genomics Goals Human Human Genetics Individual International Intervention Trial Lead Length Link Mediating Memory Mentored Research Scientist Development Award Mentors Mentorship Mission Modeling Molecular Monitor Motor Cortex Motor Neuron Disease Mutation Neurodegenerative Disorders Neurologist Other Genetics Outcome Pathogenicity Pathologic Processes Pathology Pathway interactions Patients Pattern Peripheral Phenotype Pilot Projects Production Proteins Psychiatrist Psychiatry Public Health RNA RNA Processing RNA Sequences Regulation Research Research Methodology Research Project Grants Research Training Sampling San Francisco Scientist Spinal Cord Surveys Syndrome Testing Training Universities Work aged base brain tissue career clinical phenotype cohort disease phenotype experience frontal lobe gene discovery genome wide association study genome-wide innovation neurogenetics neuropathology neuropsychiatry next generation sequencing novel protein aggregate public health relevance risk variant statistics theories tool trafficking transcriptome sequencing transcriptomics

项目摘要

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.

描述（由申请人提供）：这是加州大学旧金山记忆与衰老中心 (MAC) 神经遗传学研究员 Jennifer Yokoyama 博士的 K01 奖申请。横山博士正在将自己定位为一名年轻的遗传学家，从事神经退行性疾病的临床研究。此次K01将为Yokoyama博士提供实现以下目标所需的支持：（1）获得使用新一代测序进行转录组学的经验； (2) 精通临床研究方法，包括临床环境中遗传数据的解释； (3) 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，其中包括两名主要导师： Bruce Miller（行为神经学家，在神经退行性疾病方面拥有专业知识）和 Matthew State（人类遗传学家和儿童精神病学家，在基因发现方面拥有专业知识）；三位共同导师：博士。 Howard Rosen（具有神经退行性疾病临床研究专业知识的神经科医生）、Kristine Yaffe（具有流行病学/生物统计学专业知识的神经科医生和精神病学家）和 William Seeley（具有神经病理学专业知识的神经科医生）；和一位合作者：Giovanni Coppola 博士（一位具有人类遗传学和生物信息学专业知识的神经学家）。拟议的研究项目重点关注 C9ORF72 (C9+) 重复扩增引起的神经退行性疾病，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+ 导致表型变异（FTD 与 ALS）的生物学机制。目标 1：Yokoyama 博士将使用深度 RNA 测序确定外周 RNA 表达是否能够区分 C9+ FTD 和 C9+ ALS。目标 2：Yokoyama 博士将测试最易受 C9+ 病理影响的大脑区域中的 RNA 表达是否会根据 C9+ FTD 和 C9+ ALS 患者的 C9ORF72 扩增长度而变化。目标 3：Yokoyama 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 扩展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素并跟踪临床进展的生物标志物。拟议的研究具有创新性，因为它旨在探索基因表达变化与局部脑病理学之间的关系，并将这些变化与可能最终驱动临床疾病表现的新遗传变异联系起来。拟议研究的结果将为我们理解 C9ORF72 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丰富的生物标志物。横山博士的 K01 培训将使她做好准备，利用复杂的神经解剖表型对脑部疾病进行前沿的遗传学研究。