Immunogenetic contribution to the progression of preclinical Alzheimer's disease

免疫遗传学对临床前阿尔茨海默病进展的贡献

基本信息

批准号：
10574594
负责人：
Hyun-Sik Yang
金额：
$ 19.51万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10574594
关键词：
Acceleration Affect Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Biometry Blood specimen Cell physiology Clinical Clinical Investigator Cognitive Communities Data Data Set Dementia Disease Disease Progression Elderly Environment Evaluation Foundations Functional disorder Funding Future Gene Expression General Hospitals Generations Genes Genetic Risk Genetic Variation Genomic Segment Genomics Goals Hippocampus Hospitals Human Human Genetics Immune Immunogenetics Impaired cognition Inferior K-Series Research Career Programs Knowledge Maps Massachusetts Measures Mediating Mentors Microglia Myeloid Cells Neocortex Nerve Degeneration Neurodegenerative Disorders Outcome Study Participant Pathogenesis Pathology Phase Phenotype Play Positioning Attribute Positron-Emission Tomography Process Production Productivity Prognostic Marker Research Research Personnel Research Project Grants Research Training Resources Risk Role Sampling Scientist Technology Temporal Lobe Testing Training Translating United States National Institutes of Health Variant Woman abeta accumulation aging brain asymptomatic Alzheimer&apos s disease biomedical imaging career cell type complement pathway differential expression effective intervention effective therapy functional genomics genetic architecture genetic variant genome wide association study immune function monocyte neocortical neuroimaging marker neuroinflammation novel patient oriented research peripheral blood polygenic risk score pre-clinical predictive marker prevent preventive intervention prognostication programs risk prediction risk variant sample collection screening skills tau Proteins tau aggregation therapeutic target transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a devastating neurodegenerative disorder without an effective disease-modifying treatment. The critical role of myeloid cell in the progression of AD is supported by genome-wide association studies (GWAS) that show strong enrichment of myeloid cell gene variants in the genetic architecture of AD. However, the specific contributions of the immunogenetic variations to the AD pathogenesis and progression remain unknown. This is a particularly critical knowledge gap in preclinical AD, when an effective intervention could still prevent widespread irreversible neurodegeneration. To achieve our long-term goal of to identify therapeutic targets in preclinical AD by better understanding how immunogenetic AD risk variants affect pathophysiology, the objective of this K23 project is to identify, in preclinical AD, specific AD-relevant phenotypes that result from immunogenetic AD risk. Our central hypothesis is that higher immunogenetic AD risk predicts higher AD pathology burden, alters myeloid cell gene expression, and causes faster neurodegeneration and cognitive decline in preclinical AD. We will utilize use a specifically targeted polygenic risk score to capture the aggregate immunogenetic AD risk, and investigate our hypothesis in large samples of >4,000 clinically normal (CN) older adults from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) screening dataset and 270 CN older adults from the Harvard Aging Brain Study (HABS). We will test our hypotheses by determining the contribution of immunogentic AD risk to (1) cross-sectional AD pathology (as estimated by amyloid/tau PET) (A4/LEARN/HABS), (2) altered expression of myeloid cell gene co-expression modules (HABS), and (3) longitudinal progression of tau pathology, neurodegeneration, and cognitive decline (HABS). During his K23 Patient-Oriented Research Career Development Award period, the candidate's short-term career goal is to transition to an independent clinical investigator elucidating the clinical implications of the genetic architecture of AD, with focus on immunogenetic contribution to the progression of preclinical AD. To achieve this goal, the candidate plans to (1) gain expertise in the neuroimaging biomarkers of preclinical AD, (2) enhance genomic/transcriptomic (“omics”) data production and analysis skills, and (3) continue his training in biostatistics. By successfully executing the proposed project and training, the candidate will be in an ideal position to emerge as an independent NIH-funded clinical investigator, and achieve the long-term career goal of leading a collaborative research program to translate advances in omics into personalized prognostication and therapeutic target identification in AD. The candidate is fortunate to be in an ideal environment for his research project and training, with access to exceptional resources and research community at Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH), Martinos Center for Biomedical Imaging at MGH, and the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard.

项目概要/摘要阿尔茨海默病（AD）是一种破坏性神经退行性疾病，目前尚无有效的疾病缓解方法骨髓细胞在 AD 进展中的关键作用得到了全基因组关联的支持。研究 (GWAS) 显示 AD 遗传结构中骨髓细胞基因变异的强烈富集。然而，免疫遗传学变异对 AD 发病机制和进展的具体贡献当有效干预时，这是临床前 AD 中一个特别关键的知识差距。仍然可以预防广泛的不可逆转的神经变性，以实现我们确定的长期目标。通过更好地了解免疫遗传性 AD 风险变异如何影响临床前 AD 的治疗目标病理生理学，这个 K23 项目的目标是在临床前 AD 中识别与 AD 相关的特定免疫遗传性 AD 风险导致的表型我们的中心假设是免疫遗传性 AD 风险较高。风险预示着更高的 AD 病理负担，改变骨髓细胞基因表达，并导致更快我们将利用专门针对的多基因治疗来治疗临床前 AD 的神经退行性疾病和认知能力下降。风险评分来捕获总体免疫遗传 AD 风险，并在大样本中研究我们的假设 > 4,000 名临床正常 (CN) 老年人接受抗淀粉样蛋白治疗无症状 AD (A4) 淀粉样蛋白风险和神经变性 (LEARN) 筛查数据集的研究/纵向评估和 270 来自哈佛大脑老化研究 (HABS) 的 CN 老年人我们将通过确定以下值来检验我们的假设。免疫原性 AD 风险对 (1) AD 横断面病理学的影响（通过淀粉样蛋白/tau PET 估计） (A4/LEARN/HABS)，(2) 骨髓细胞基因共表达模块 (HABS) 的表达改变，以及 (3) K23 期间 tau 蛋白病理学、神经变性和认知能力下降 (HABS) 的纵向进展。以患者为中心的研究职业发展奖期间，候选人的短期职业目标是转变为独立临床研究者，阐明遗传结构的临床意义 AD 的研究，重点是免疫遗传学对临床前 AD 进展的贡献。候选人计划 (1) 获得临床前 AD 神经影像生物标志物方面的专业知识，(2) 增强基因组/转录组（“组学”）数据生成和分析技能，以及 (3) 继续接受以下方面的培训：通过成功执行拟议的项目和培训，候选人将处于理想状态。成为 NIH 资助的独立临床研究者，并实现长期职业目标领导一项合作研究计划，将组学进展转化为个性化预后以及 AD 治疗目标的确定该候选人很幸运能够处于一个理想的环境中。研究项目和培训，可以获得布里格姆和研究社区的特殊资源和研究社区妇女医院 (BWH)、马萨诸塞州综合医院 (MGH)、马蒂诺斯生物医学成像中心 MGH、麻省理工学院 (MIT) 和哈佛大学布罗德研究所。