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: 10686043
• 负责人: Jesse N Cochran
• 金额: $ 23.47万
• 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/10686043
• 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; Categories; Cellular biology; Chromosome Mapping; Classification; Code; Complement; Complex; Coupled; Data Science; Data Set; Databases; Disease; Educational process of instructing; Enhancers; Environment; Etiology; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Genomic approach; Genomics; Goals; Human; Huntington gene; Infrastructure; Knowledge; Label; 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; career development; cell type; chromatin immunoprecipitation; data integration; disorder risk; experimental study; frontotemporal lobar dementia amyotrophic lateral sclerosis; functional genomics; gain of function; 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; skills; 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 这个NIH独立之路奖的目标是为J.尼古拉斯（尼克）科克伦博士提供 一个全面的培训计划，准备他成为一个领先的独立调查员谁使用基因组 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， 先进的统计学和先进的数据科学，以补充科克伦博士十多年的培训， 在神经科学和基因组学领域获得的最新研究成果基因组测序研究继续提供新的 与疾病的统计学关联，但迄今为止，非编码变异在很大程度上被忽视。一个关键 将罕见的非编码变异纳入负担分析和进一步研究 转录复合物或疾病相关细胞生物学上的那些变体在历史上一直缺乏一种 正确分类非编码变异的影响并将其确定为疾病相关的能力。的 PI在最近的一项研究中提出了一种使用计算滤波来解决这一障碍的方法， 这里的目标将允许进一步的机制完善的方法，以评估功能的后果， 神经退行性疾病的罕见非编码变异。除了可以发现更多的基因- 疾病相关性，疾病相关非编码变异的位置将告知生物学如何 靶基因受到调控（结果提供了对疾病病因的了解），甚至可以提供 通过提供三维蛋白质的证据，支持新的治疗途径， 控制疾病相关基因表达的复合物，如果理解得足够好， 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，鉴于 在该提案中，PI特别提出（1）通过实验来了解调节和罕见变异的影响 MAPT（编码tau蛋白，这是许多神经退行性疾病中的关键蛋白质），（2）实验， 提供与以下统计学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，通过病例对照研究确定神经退行性疾病，以及（3） 用β淀粉样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 治疗作为一个原则的证明。导师和共同导师是遗传学和基因组学领域的领导者，博士。 Richard Myers（HudsonAlpha）和Gregory库珀博士（HudsonAlpha）。科克伦博士还组织了一个 神经变性领域的领导人委员会，包括Kenneth Kosik博士（UCSB），Erik Roberson博士 (UAB)和詹妮弗·横山博士（加州大学旧金山分校），他们都采用遗传学和基因组学方法在他们的研究中， 工作指导阶段将在哈德逊阿尔法生物技术研究所进行，该研究所是一家非营利性研究机构， 和教学机构的理想环境和基础设施，以支持这一功能基因组学项目。 总之，拟议的研究将允许科克伦博士磨练他的功能基因组学技能，因为他 转变为独立调查员的角色。

项目成果

Neuronal MAPT expression is mediated by long-range interactions with cis-regulatory elements.

• DOI: 10.1016/j.ajhg.2023.12.015
• 发表时间: 2024-01
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: B. Rogers;Ashlyn G. Anderson;Shelby N. Lauzon;M. N. Davis;Rebecca M. Hauser;Sydney C. Roberts;Ivan Rodriguez-Nunez;Katie Trausch-Lowther;Erin A. Barinaga;Paige I Hall;Matthew T Knuesel;Jared W Taylor;M. Mackiewicz;Brian S. Roberts;Sara J. Cooper;Lindsay F. Rizzardi;R. M. Myers;J. N. Cochran

Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer's disease-specific cis-regulatory elements.

• DOI: 10.1016/j.xgen.2023.100263
• 发表时间: 2023-03-08
• 期刊: CELL GENOMICS
• 作者: Anderson, Ashlyn G.;Rogers, Brianne B.;Loupe, Jacob M.;Rodriguez-Nunez, Ivan;Brazell, J. Nicholas;Roberts, Sydney C.;White, Lauren M.;Bunney, William E.;Bunney, Blynn G.;Watson, Stanley J.;Cochran, J. Nicholas;Myers, Richard M.;Rizzardi, Lindsay F.
• 通讯作者: Rizzardi, Lindsay F.