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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

项目总结/文摘