Understanding the role of genetic admixture on Alzheimer’s Disease risk in Latíno Populations

了解基因混合对拉丁裔人群阿尔茨海默病风险的影响

• 批准号: 10665080
• 负责人: Esteban M Lucero
• 金额: $ 8.32万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665080
• 关键词: ATP phosphohydrolase; Acute; Address; Admixture; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein; Animals; Architecture; Award; BRAIN initiative; Behavioral; Biochemical; Biological Assay; Biological Models; Brain; Caregivers; Cell Culture Techniques; Cell physiology; Cognitive; Defect; Dendritic Spines; Deposition; Depressed mood; Development; Disease; Disease Progression; Doctor of Philosophy; Elderly; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; Grant; Haplotypes; Health; Healthcare Systems; Hippocampus; In Vitro; Individual; Investigation; Kinesin; Knowledge; Latino Population; Leadership; Learning; Link; Long-Term Potentiation; Longevity; Measurement; Mediating; Memory; Memory impairment; Mentors; Mentorship; Microtubule Polymerization; Microtubules; Morphology; Motor; Mus; Neurites; Neurodegenerative Disorders; Neurons; Neurosciences; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Population; Postdoctoral Fellow; Prevention; Process; Proteins; Public Health; Research; Research Personnel; Research Project Grants; Role; Route; Slice; Symptoms; Testing; Therapeutic Intervention; United States National Institutes of Health; Vertebral column; Wild Type Mouse; Work; Writing; abeta oligomer; aged; career; clinically significant; conditioned fear; density; disease phenotype; effective therapy; experimental study; healthspan; improved; innovation; interest; mouse model; nervous system disorder; neural; novel; novel therapeutic intervention; overexpression; prevent; skills; small molecule; therapeutic target

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) currently affects more than 5 million Americans and is a significant burden for patients, caregivers, and our healthcare system. Currently, there is no known cure for AD, and approved therapies do not reverse the underlying pathogenesis or inhibit disease progression. Amyloid deposits and their associated amyloid beta oligomers (Aβ) are linked to multiple cellular dysfunctions in the brains of AD patients and in animal and cell culture models of AD. Some of these dysfunctions include microtubule instability, loss of dendritic spine density, and depressed hippocampal long-term potentiation (LTP). Many hypotheses have been put forward to explain the routes by which Aβ contributes to these phenotypes. However, a unified mechanistic understanding has not yet been achieved. This project builds on previous studies that have shown that Aβ inhibits the activity of a select set of microtubule motor proteins. Among them, Kinesin-5/EG5/KIF11 is of particular interest due to its diverse functions, which include regulating microtubule stability, microtubule polymerization, and dendritic architecture, all of which are negatively impacted by Aβ. Based on these findings, the long-term goal of this project is to determine whether Kinesin-5 activity may serve as an effective target for preventing or reversing A β -induced AD phenotypes: 1) by overexpressing Kinesin-5 to maintain its activity, or 2) by using small molecule drugs we identified in a screen that block Aβ-mediated inhibition of Kinesin-5 activity. In order to address these goals we are using a mouse model system in combination with cell culture and biochemical tests that aim to 1) Determine whether Kinesin-5 overexpression improves learning and memory in a wild-type mouse without AD pathology and whether Kinesin-5 overexpression rescues Aβ-induced AD phenotypes in the an AD mouse model; 2) Determine whether Kinesin-5 overexpression improves long-term potentiation (LTP) and whether deficits in LTP caused by Aβ are rescued by Kinesin-5 overexpression; and 3) Determine whether Kinesin-5 overexpression impacts neural process outgrowth, spine density, and morphology in wild-type and 5xFAD mice. Our proposed research will also provide an increased understanding of the role of Kinesin-5 activity in regulating diverse neuronal processes. The clinical significance of this work comes from the identification of underlying mechanisms linked to aberrant cellular functions that may uncover an entirely new therapeutic approach to AD. The innovative aspects of this project are rooted in the identification of Kinesin-5 as a potential therapeutic target for the treatment of AD and include: 1) interrogating of as yet uncharacterized functions of Kinesin-5 in learning, memory, and AD-related phenotypes; and 2) pursuing an entirely new avenue of investigation into desperately needed AD treatments using Kinesin-5 activity as a therapeutic target.

项目摘要/摘要 阿尔茨海默氏病（AD）目前影响超过500万美国人 患者，看护者和我们的医疗保健系统。目前，尚无广告的已知治疗方法，并获得了批准 疗法不会扭转潜在的发病机理或抑制疾病进展。淀粉样蛋白沉积物和 它们相关的淀粉样蛋白β低聚物（Aβ）与AD的大脑中的多个细胞功能障碍有关 患者以及AD的动物和细胞培养模型。其中一些功能障碍包括微管 不稳定性，树突状脊柱密度的丧失和海马长期增强（LTP）。许多 已经提出了假设来解释Aβ对这些表型有助于的途径。 但是，尚未实现统一的机械理解。这个项目建立在以前的 研究表明Aβ抑制了一组微管运动蛋白的活性。他们之中， 驱动蛋白-5/EG5/KIF11由于其潜水功能特别感兴趣，其中包括调节微管 稳定性，微管聚合和树突结构，所有这些结构都受Aβ的负面影响。 基于这些发现，该项目的长期目标是确定动力蛋白5活动是否可能 作为预防或逆转β诱导的AD表型的有效目标：1） 过表达驱动蛋白5以维持其活性，或2）使用小分子药物我们在A中鉴定 筛选Aβ介导的抑制驱动蛋白-5活性。为了解决这些目标，我们是 使用小鼠模型系统与细胞培养和旨在的生化测试结合使用1） 动力蛋白-5的过表达是否可以改善没有AD病理的野生型鼠标中的学习和记忆 并且动力蛋白-5的过表达是否在AD小鼠模型中挽救Aβ诱导的AD表型； 2） 确定驱动蛋白5的过表达是否改善了长期增强（LTP）以及缺陷是否存在 由Aβ引起的LTP由驱动蛋白5的过表达挽救； 3）确定驱动蛋白-5是否 过表达会影响野生型和5xFAD的神经过程的产物，脊柱密度和形态 老鼠。我们拟议的研究还将越来越多地了解驱动蛋白5活动在 调节潜水员神经元过程。这项工作的临床意义来自于确定 与异常细胞功能相关的基本机制可能会发现全新的疗法 广告的方法。该项目的创新方面源于识别驱动蛋白5作为一个 AD治疗的潜在治疗靶标，包括：1）询问AS尚未表征 驱动蛋白5在学习，记忆和与广告相关的表型中的功能； 2）追求全新 使用Kinesin-5活动作为治疗目标，对迫切需要广告处理的投资大道。