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: 10470973
• 负责人: Jesse N Cochran
• 金额: $ 24.9万
• 依托单位: HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470973
• 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 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.

摘要 NIH独立之路奖的目标是为J.Nicholas(Nick)Cochran博士提供 一个全面的培训计划，让他成为一名领先的独立调查员，利用基因组 研究神经退行性疾病的方法。我们建议进行为期一年的功能基因组学培训， 高级统计和高级数据科学，以补充Cochran博士十多年的培训 在神经科学和基因组学领域获得了最新成果。基因组测序研究继续提供新的 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了。一位批评者 阻碍将罕见的非编码变化纳入负担分析，并进一步研究 这些转录复合体或疾病相关细胞生物学的变体历来缺乏 能够正确地对非编码变体的影响进行分类，并将其确定为与疾病相关。这个 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 此处的目标将允许进一步机械地细化方法，以评估 神经退行性疾病罕见的非编码变异。除了允许发现更多的基因- 疾病关联，与疾病相关的非编码变异的位置将告知生物学如何 靶基因是受调控的(结果是提供了对疾病病因的洞察)，甚至可以提供 通过为三维蛋白质提供证据支持新的治疗途径以供考虑 控制疾病相关基因表达的复合体，如果理解得足够好，可能是 可下药的。这将对任何基因疾病关联具有广泛的适用性。然而，考虑到 在这项建议中，PI具体提出(1)实验以了解规则和罕见的变异影响 关于MAPT(它编码tau，一种在许多神经退行性疾病中的关键蛋白质)，(2)实验 提供统计上相关的罕见非编码变异的真阳性和真阴性训练集 神经退行性疾病的病例对照研究，通过对这些变异进行功能分析，以及(3) 用淀粉样β蛋白阐明罕见的非编码变异对疾病相关刺激的影响的实验 将治疗作为一种原则证明。这位导师和共同导师是遗传学和基因组学领域的领导者。 理查德·迈尔斯(HudsonAlpha饰)和格雷戈里·库珀博士(HudsonAlpha饰)。科克伦博士还组装了一个 神经变性领域领导委员会，包括肯尼斯·科西克博士(UCSB)、埃里克·罗伯逊博士 (UAB)和詹妮弗·横山博士(UCSF)，他们都在他们的研究中使用了遗传学和基因组学方法 工作。指导阶段将在非营利性研究机构哈德逊·阿尔法生物技术研究所进行 和教学机构拥有理想的环境和基础设施来支持这一功能基因组学项目。 总之，拟议的研究将使科克伦博士能够在他的工作中磨练他的功能基因组学技能。 过渡到独立调查员的角色。