Individual Predoctoral Fellowship

个人博士前奖学金

• 批准号: 10752036
• 负责人: Breanna Dooling
• 金额: $ 3.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-02-02 至 2027-02-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752036
• 关键词: Acceleration; Adult; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Apolipoproteins; Astrocytes; Biological Models; Brain; Brain Pathology; Cerebrum; Chromosome 21; Clinical; Clinical Trials; Cohort Studies; Communities; Conceptions; Dementia; Development; Down Syndrome; Effectiveness; Environmental Risk Factor; Fellowship; Future; Gene Proteins; Genes; Genetic; Genotype; Goals; Human; Impaired cognition; Individual; Investigation; Measures; Mediating; Microglia; Modeling; Morphology; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Observational Study; Organoids; Pathologic; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Polymers; Population; Prosencephalon; Proteins; Publishing; Quality of life; Relative Risks; Research; Risk; Risk Factors; Risk Reduction; Role; Senile Plaques; Severities; Severity of illness; Testing; Therapeutic; Treatment Efficacy; Variant; apolipoprotein E-3; apolipoprotein E-4; brain cell; cell type; cohort; disease phenotype; drug candidate; effective therapy; efficacy evaluation; experimental study; extracellular; familial Alzheimer disease; genetic variant; improved; induced pluripotent stem cell; inhibitor; neurodegenerative phenotype; neuroinflammation; neuropathology; novel; novel therapeutic intervention; novel therapeutics; polymerization; pre-doctoral; prevent; small molecular inhibitor; small molecule; small molecule inhibitor; stem cell model; tau aggregation; tau-1; therapeutic target; tool

ABSTRACT Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tau tangles (NFTs) which together contribute to neuroinflammation, neurodegeneration, and often cognitive decline. Down syndrome (DS) is the result of having three copies of chromosome 21 (T21) from conception. The Aβ peptide is a cleavage product of the amyloid precursor protein (APP) which is encoded by the APP gene. Given that the APP gene resides on chromosome 21, all people with DS accumulate higher levels of Aβ peptide in their brains. Accordingly, adults with DS will develop AD pathology (DS-AD), and many go on to develop clinical dementia. DS-AD has documented pathological differences from typical AD, including accelerated Aβ and tau accumulation and a more heterogeneous Aβ plaque composition. While there are numerous genetic and environmental contributors to AD risk, the APOE gene, and especially the ε4 variant (APOE4), has been identified as the greatest risk factor for typical AD besides age itself. Inheritance of APOE4 also significantly increases risk for AD and cognitive decline in individuals with DS. Cohort studies in people with DS have found an overall increased AD risk conferred by APOE4, but investigations of the mechanistic role of APOE4 in people with DS are lacking. Clearly, there is an urgent need for studies interrogating the mechanism of increased risk of AD for people with DS carrying APOE4. The overall goal of this proposal is to elucidate the role of the APOE4 genotype in the development of DS-AD and assess the potential of apoE4-drive Aβ fibrilization as a therapeutic target. Specifically, I will identify APOE4- driven mechanisms and pathways that contribute to the development of DS-AD neuropathologies and assess the efficacy of small molecular inhibitors of apoE and/or Aβ in alleviating these pathologies. To accomplish these goals, I will develop novel human induced pluripotent stem cell (hiPSC)-based models of DS-AD that carry APOE4. I will generate multiple human neural cell types and cerebral organoids (COs) from the hiPSCs to determine the specific effects of APOE4 in these models of the developing and aging human DS-AD brain. I will evaluate six validated small molecule drugs that have been shown to prevent and/or reverse apoE4-catalyzed Aβ fibrillization in my CO model system. My overall hypothesis is that APOE4 will accelerate and enhance the development of AD neuropathologies in hiPSC-based models of DS-AD and can be targeted with small molecule apoE inhibitors to alleviate those AD phenotypes.

抽象的 阿尔茨海默氏病是一种神经退行性疾病，其特征是细胞外淀粉样蛋白的积累 β（Aβ）斑块和细胞内神经原纤维tau缠结（NFTS），共同有助于 神经炎症，神经退行性变化以及经常认知能力下降。唐氏综合症（DS）是具有 概念的三副染色体21（T21）。 AβPeelede是淀粉样蛋白的裂解产物 由APP基因编码的前体蛋白（APP）。鉴于染色体上的应用基因住宅 21，所有DS的人在大脑中均积累较高水平的Aβ肽。彼此之间，DS成年人将 发展AD病理学（DS-AD），许多人继续发展临床痴呆。 DS-AD已记录 与典型AD的病理差异，包括加速Aβ和TAU加速度以及更多 异质Aβ斑块组成。尽管有许多遗传和环境贡献者 风险，APOE基因，尤其是ε4变体（APOE4），已被确定为最大的风险因素 除了年龄本身，典型的广告。 APOE4的继承也大大增加了AD和认知下降的风险 在患有DS的个体中。对DS患者的队列研究发现 APOE4，但是缺乏对APOE4在DS患者中的机械作用的研究。显然，有一个 迫切需要进行研究，以询问携带APOE4的DS患者的AD风险增加的机制。 该提案的总体目标是阐明APOE4基因型在DS-AD发展中的作用 并评估APOE4-DRIVEAβ纤维化作为治疗靶标的潜力。具体来说，我将确定apoe4-- 驱动的机制和途径有助于发展DS-AD神经病理学和评估 APOE和/或Aβ的小分子抑制剂在减轻这些病理方面的效率。完成这些 目标，我将开发新型人类诱导的多能干细胞（HIPSC）基于DS-AD的模型 APOE4。我将产生多种人类神经细胞类型和脑器官（COS）从hipsc到 在这些发展中和衰老的人DS-AD大脑的这些模型中，确定APOE4的特定效果。我会 评估已证明可以预防和/或反向APOE4催化的六种经过验证的小分子药物 我的CO模型系统中的Aβ纤维化。我的总体假设是APOE4将加速并增强 基于HIPSC的DS-AD模型中AD神经病理学的发展，可以针对 小分子APOE抑制剂可减轻这些AD表型。