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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的这项NIH独立奖的目标是为J. Nicholas（Nick）Cochran博士提供一项全面的培训计划，使他成为使用基因组的领先独立调查员的准备研究神经退行性疾病的方法。我们建议一年的功能基因组学培训，高级统计数据和高级数据科学，以补充科克伦博士的十年培训迄今为止在神经科学和基因组学中收到。基因组测序研究继续提供新的统计与疾病的关联，但迄今为止，非编码变化已在很大程度上被忽略了。批判将罕见的非编码变化纳入负担分析的障碍，并进一步研究这些关于转录复合物或与疾病相关的细胞生物学的变体历史上缺乏能够正确分类非编码变体的效果并将其确定为疾病相关的能力。这 PI在最近的一项研究中提出了一种使用计算过滤解决此障碍的方法，此处的目的将允许进一步的方法来评估方法来评估功能后果神经退行性疾病的罕见非编码变化。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体的位置将告知生物学对靶基因进行调节（结果提供了疾病病因的见解），甚至可以提供通过提供三维蛋白的证据来支持新的治疗途径以考虑考虑控制疾病相关基因表达表达的复合物，如果理解得足够好，可能是可吸毒。这对于任何基因疾病关联都有广泛的适用性。但是，考虑到重点 PI专门提出了这一建议，（1）实验以了解调节和罕见变体影响关于MAPT（在许多神经退行性疾病中的关键蛋白质tau编码）上，（2）实验提供与稀有非编码变化的真正积极和真正的负面训练集，统计与通过对这些变体进行功能测定的病例对照研究的神经退行性疾病，（3）阐明罕见的非编码变化对疾病相关刺激的影响，淀粉样蛋白β 作为原则证明的治疗。导师和同事是遗传学和基因组学领域的领导者，博士。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神经退行性领域的领导委员会，包括Kenneth Kosik博士（UCSB），Erik Roberson博士（UAB）和Jennifer Yokoyama博士（UCSF），所有这些人都采用遗传学和基因组学方法工作。指导阶段将在非营利性研究的Hudsonalpha生物技术研究所举行以及具有理想环境和基础设施的教学研究所，以支持这个功能基因组学项目。总而言之，拟议的研究将使科克伦博士在他的功能基因组技能方面磨练他的功能性基因组技能过渡到独立研究者角色。