T-cell receptor repertoires and Alzheimer's disease

T 细胞受体库和阿尔茨海默病

基本信息

批准号：
9918835
负责人：
DANA C CRAWFORD
金额：
$ 16.07万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2019-05-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918835
关键词：
Adult Affect Aging Alleles Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amish Amyloid beta-Protein Amyloid deposition Animal Model Basic Science Binding Biological Blood Vessels Bone Marrow Transplantation Brain Cause of Death Cholesterol Clinical Trials Clonality Communities Data Deposition Development Disease Disease Progression Dose Drug Targeting Education Elderly Etiology Exhibits Functional disorder Funding Future Genes Genetic Genetic Diseases Genetic Risk Genetic study Genomic DNA Goals Health Health Status Health education Human Immune Immune response Immune system Impaired cognition Indiana Individual Innate Immune Response Late Onset Alzheimer Disease Life Style Measures Memory Memory Loss Memory impairment Mental Depression Mentors Mus Names Natural Immunity Natural Killer Cells Neurodegenerative Disorders Ohio Pathway interactions Phase III Clinical Trials Phenotype Physical activity Pilot Projects Population Positioning Attribute Prevention Prevention strategy Process Psyche structure Research Research Personnel Resources Risk Risk Factors Sampling Secondary Prevention Senile Plaques Smoking Source Study models Suggestion T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Therapeutic United States Variant adaptive immune response adaptive immunity aging population apolipoprotein E-4 base beta Chain Antigen T Cell Receptor beta amyloid pathology burden of illness case control design disorder control drug discovery epidemiology study forging genetic risk factor genetic variant genome sequencing genome wide association study genome-wide genome-wide analysis genomic data humanized monoclonal antibodies mental function modifiable risk neuroinflammation next generation next generation sequencing pre-clinical prevent prospective recruit response risk variant therapy development treatment response treatment strategy whole genome

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is a major cause of death and a significant source of financial and health burden among the elderly. There is no cure for AD. With the number of US adults ≥65 doubling in the coming years, the need for better prevention and treatment strategies is paramount. Epidemiologic and genetic studies have identified several modifiable (e.g., vascular health, education, physical activity, mental activity, to name a few) and non- modifiable risk factors associated with AD risk. The strongest genetic risk factor identified to date for late-onset AD is the APOE e4 allele. APOE regulates cholesterol in the brain, and it binds to the amyloid-β peptide, a known major component of amyloid plaques found in AD patients. Major drug discovery efforts have focused on the amyloid-β and neuroinflammation pathways based on, in part, these basic AD discovery efforts, but no therapies have emerged that prevent or substantially change the trajectory of disease development among early AD patients. New basic discovery studies are needed to better understand the etiology and pathophysiology of AD to create new avenues of drug targets. Variability in the immune system’s response is an emerging factor in the development of AD. AD genome-wide studies reflect an enrichment of genes related to the innate and adaptive immune response, and animal models further suggest that the lack of immune response leads to an increase in amyloid-β pathology, a phenotype that can be rescued with bone marrow transplantation. While some basic research on the genetic variants related to the innate immune response has been performed, no research to date has focused on the extreme somatic diversity of the adaptive immune response and its relationship with AD. We propose here as new investigators to AD research a pilot study to characterize the T-cell repertoire among Amish AD cases and controls. We will leverage local AD resources that include ongoing AD and successful aging studies recruiting Amish living in Ohio and Indiana who are ≥80 years old. These resources also include existing genome-wide data from arrays and next-generation sequencing as well as imputation based on whole genome sequencing data. As important, the local resources are drawn from an active AD collaborative community eager to mentor and support new investigators forging original lines of research that potentially contribute to the prevention and/or treatment of disease. Against this backdrop, we propose the sequence the T-cell receptor beta (TCRB) chain of 30 Amish AD cases and 30 controls to characterize TCR diversity and its possible relationship with AD. These data will serve as key pilot data for larger studies of the adaptive immune response in the prospective and newly funded Collaborative Amish & Aging Memory Project (CAAMP) as well as future studies in diverse outbred populations.

项目概要阿尔茨海默病 (AD) 是死亡的主要原因，也是经济和健康负担的重要来源 AD 无法治愈，未来几年美国 65 岁以上成年人的数量将增加一倍。流行病学和遗传学研究已确定更好的预防和治疗策略至关重要。一些可改变的（例如，血管健康、教育、体力活动、精神活动等）和不可改变的与 AD 风险相关的可改变的风险因素是迄今为止发现的晚发性最强的遗传风险因素。 AD 是 APOE e4 等位基因，它调节大脑中的胆固醇，它与淀粉样蛋白-β 肽结合。 AD 患者中发现的淀粉样蛋白斑块的已知主要成分已成为主要药物发现工作的重点。关于淀粉样蛋白-β 和神经炎症途径的研究部分基于这些基本的 AD 发现工作，但没有已经出现了可以预防或显着改变早期疾病发展轨迹的疗法 AD 患者需要新的基础研究来更好地了解 AD 的病因和病理生理学。 AD创造药物靶点的新途径。免疫系统反应的变异性是 AD 全基因组发展的一个新兴因素。研究反映了与先天性和适应性免疫反应以及动物模型相关的基因的丰富进一步表明，免疫反应的缺乏会导致淀粉样蛋白-β病理学的增加，这是一种表型可以通过骨髓移植来挽救，而有关遗传变异的一些基础研究。已经进行了先天免疫反应，迄今为止还没有研究关注极端的体细胞反应适应性免疫反应的多样性及其与 AD 的关系。我们在此建议作为 AD 研究的新研究者进行一项试点研究，以表征 T 细胞库阿米什 AD 案例和控制措施我们将利用当地 AD 资源，包括正在进行的 AD 和成功的 AD 资源。老龄化研究招募了居住在俄亥俄州和印第安纳州的 80 岁以上的阿米什人。这些资源还包括。来自阵列和下一代测序的现有全基因组数据以及基于整体的插补同样重要的是，本地资源来自活跃的 AD 合作。社区渴望指导和支持新的研究人员，打造具有潜在潜力的原创研究路线在此背景下，我们提出了以下顺序： 30 个阿米什 AD 病例和 30 个对照的 T 细胞受体 β (TCRB) 链，用于表征 TCR 多样性及其这些数据将作为更大范围的适应性免疫研究的关键试点数据。前瞻性和新资助的阿米什与衰老记忆合作项目（CAAMP）的回应作为未来对不同近交种群的研究。