Regulatory mechanisms of rare non-coding variation in neurodegeneration-associated loci

神经退行性变相关位点罕见非编码变异的调控机制

• 批准号: 10031002
• 负责人: Jesse N Cochran
• 金额: $ 11.83万
• 依托单位: HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10031002
• 关键词: 3-Dimensional; Address; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Award; Basic Science; Bioinformatics; Biological Assay; Biology; Biotechnology; Candidate Disease Gene; Case-Control Studies; Cellular biology; Chromosome Mapping; Cleaved cell; Code; Complement; Complex; Coupled; Data Science; Data Set; Databases; Disease; Educational process of instructing; Enhancers; Environment; Etiology; Future; Gene Expression; Gene Expression Regulation; Gene Proteins; Gene Targeting; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Genomic approach; Genomics; Goals; Human; Huntington gene; Infrastructure; Institutes; Knowledge; Location; Measures; Mentors; Microglia; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Nucleic Acid Regulatory Sequences; Outcome; Pathogenicity; Pathologic; Pathway interactions; Phase; Positioning Attribute; Privatization; Production; Proteins; Regulation; Regulatory Element; Reporter; Repression; Research; Research Personnel; Resources; Risk Assessment; Role; Running; Scientist; Sensitivity and Specificity; Signal Transduction; Stimulus; System; Testing; Therapeutic; Training; Training Programs; United States National Institutes of Health; Untranslated RNA; Variant; Work; alpha synuclein; base; career development; cell type; chromatin immunoprecipitation; data integration; disorder risk; experimental study; frontotemporal lobar dementia-amyotrophic lateral sclerosis; functional genomics; genetic approach; genetic profiling; genetic variant; genome sequencing; genome wide association study; improved; insight; loss of function; nerve stem cell; novel strategies; novel therapeutics; programs; promoter; protein complex; rare variant; recruit; statistics; success; tau Proteins; therapeutic development; transcription factor; transcriptome sequencing

Abstract The goal of this NIH Pathway to Independence award is to provide Dr. J. Nicholas (Nick) Cochran with a comprehensive training program to prepare him to be a leading independent investigator who uses genomic approaches to study neurodegenerative disease. We propose one year of training in functional genomics, advanced statistics, and advanced data science to complement over ten years of training that Dr. Cochran has received to date in neuroscience and genomics. Genome sequencing studies continue to provide new statistical associations with disease, but to date non-coding variation has been largely disregarded. A critical barrier to incorporating rare non-coding variation into burden analyses and to further studying the effects of those variants on transcriptional complexes or disease-related cell biology has historically been a lack of an ability to properly categorize the effect of non-coding variants and establish them as disease-associated. The PI has put forward one approach to address this barrier using computational filtering in a recent study, and the aims here will allow for further mechanistic refinement of approaches to assess the functional consequences of rare non-coding variation for neurodegenerative diseases. In addition to allowing for discovery of more gene- disease associations, the location of disease-associated non-coding variants will inform on the biology of how the target genes are regulated (resultantly providing insight into disease etiology), and could even provide support for new therapeutic avenues for consideration by providing evidence for the three dimensional protein complexes controlling expression of disease associated genes, which, if understood well enough, may be druggable. This would have broad applicability for any gene-disease association. However, given the focus of this proposal, the PI specifically proposes (1) experiments to understand regulation and rare variant influences on MAPT (which codes for tau, a critical protein in many neurodegenerative diseases), (2) experiments to provide true positive and true negative training sets of rare non-coding variation statistically associated with neurodegenerative diseases by case-control studies by performing functional assays on these variants, and (3) experiments to elucidate rare non-coding variation influences on disease associated stimuli, with amyloid beta treatment as a proof-of-principle. The mentor and co-mentor are leaders in the genetics and genomics field, Dr. Richard Myers (HudsonAlpha) and Dr. Gregory Cooper (HudsonAlpha). Dr. Cochran has also assembled a committee of leaders in the neurodegeneration field including Dr. Kenneth Kosik (UCSB), Dr. Erik Roberson (UAB), and Dr. Jennifer Yokoyama (UCSF), all of whom employ genetics and genomics approaches in their work. The mentored phase will take place at the HudsonAlpha Institute for Biotechnology, a non-profit research and teaching institute with an ideal environment and infrastructure to support this functional genomics project. In summary, the proposed studies will allow for Dr. Cochran to hone his functional genomics skillset as he transitions into an independent investigator role.

抽象的 NIH 独立之路奖的目标是为 J. Nicholas (Nick) Cochran 博士提供 全面的培训计划，使他成为一名使用基因组学的领先独立研究者 研究神经退行性疾病的方法。我们建议进行一年的功能基因组学培训， 先进的统计学和先进的数据科学补充了 Cochran 博士十多年的培训 迄今为止在神经科学和基因组学领域获得的成果。基因组测序研究不断提供新的 与疾病的统计关联，但迄今为止，非编码变异在很大程度上被忽视。一个批评的 将罕见的非编码变异纳入负担分析以及进一步研究其影响的障碍 转录复合物或疾病相关细胞生物学上的这些变异历来缺乏 正确分类非编码变异的影响并将其确定为与疾病相关的能力。这 PI 在最近的一项研究中提出了一种使用计算过滤来解决这一障碍的方法，并且 这里的目标将允许进一​​步机械完善评估功能后果的方法 神经退行性疾病的罕见非编码变异。除了允许发现更多基因之外 疾病关联，与疾病相关的非编码变异的位置将在生物学上提供信息 靶基因受到调节（从而提供对疾病病因学的深入了解），甚至可以提供 通过为三维蛋白提供证据来支持新的治疗途径供考虑 控制疾病相关基因表达的复合物，如果充分理解的话，可能是 可下药的。这对于任何基因疾病关联都有广泛的适用性。然而，考虑到焦点 在该提案中，PI特别提出（1）通过实验来了解监管和罕见变异的影响 MAPT（编码 tau 蛋白，这是许多神经退行性疾病中的一种关键蛋白），(2) 实验 提供与统计相关的罕见非编码变异的真阳性和真阴性训练集 通过对这些变体进行功能测定来进行病例对照研究的神经退行性疾病，以及 (3) 阐明罕见非编码变异对疾病相关刺激的影响的实验，β淀粉样蛋白 作为原理验证的处理。导师和共同导师都是遗传学和基因组学领域的领导者，Dr. 理查德·迈尔斯 (HudsonAlpha) 和格雷戈里·库珀博士 (HudsonAlpha)。科克伦博士还组装了一个 由神经退行性疾病领域的领导者组成的委员会，包括 Kenneth Kosik 博士 (UCSB)、Erik Roberson 博士 （UAB）和 Jennifer Yokoyama 博士（UCSF），他们都在他们的研究中采用了遗传学和基因组学方法。 工作。指导阶段将在 HudsonAlpha 生物技术研究所进行，该研究所是一家非营利性研究机构 和教学机构，拥有理想的环境和基础设施来支持该功能基因组学项目。 总之，拟议的研究将使 Cochran 博士能够磨练他的功能基因组学技能。 转变为独立调查员的角色。