Genetic dissection of dementia

痴呆症的基因剖析

• 批准号: 10412678
• 负责人: Kyung-An Han
• 金额: $ 15.3万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-13 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412678
• 关键词: Acetylcholine; Address; Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease related dementia; American; Amyloid; Animal Model; Biomedical Research; Candidate Disease Gene; Caregivers; Chronic Disease; Communities; Consumption; DNA Sequence Alteration; Deletion Mutation; Dementia; Development; Disease; Dissection; Drosophila genus; Drosophila melanogaster; Economic Burden; Elderly; Enzymes; Etiology; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Crosses; Genetic Screening; Goals; Hispanic Populations; Insertion Mutation; Intercistronic Region; Introns; Knowledge; Link; Mammals; Measures; Memory; Memory Loss; Mutation; Nerve Degeneration; Neurosciences Research; Oxidative Stress; Pathogenicity; Point Mutation; Prevalence; Prevention; Process; Progressive Disease; RNA Interference; Research; Research Training; Rest; Rodent Model; Role; Sleep Deprivation; Societies; Students; Symptoms; Synapses; Tauopathies; Testing; Therapeutic; Time; Training and Education; Transgenic Organisms; X Chromosome; age related; biological research; caucasian American; combat; conditioning; cost; cost effective; dopaminergic neuron; endophenotype; executive function; fly; gene discovery; gene function; genetic risk factor; genome wide association study; genomic locus; health economics; human old age (65+); innovation; insight; mutant; non-genetic; relating to nervous system; screening; social factors; social stress; tau aggregation; tool

Project Abstract The major goal of this research is to identify the genetic risk factors with functional significance to dementia in the model organism Drosophila melanogaster. The key aspect of dementia is age- dependent neurodegeneration that cripples executive functions (e.g. inhibitory control) and memory. Most dementia studies have focused on memory loss, which is a prominent symptom of AD - the most common dementia type. While animal models have provided important insights into the mechanism for memory loss, their utility for dementia gene discovery is limited since the study of memory loss is time-consuming and laborious. Executive deficits are major symptoms in early stage AD and related dementias yet largely understudied. We overcome these limitations by studying inhibitory control deficit as a dementia endophenotype for the discovery of dementia genes, which is innovative. Our approach is to conduct an unbiased screen for the genetic loci causing dysfunctional inhibitory control in an age-dependent manner, with or without the non- genetic risk factors. In this proposal we will also test the hypothesis that the genetic and non- genetic risk factor interaction has a greater effect on dementia than a genetic factor alone. Drosophila is tractable for student research training and education as it is easy to handle, allows to readily apply state-of-the-art tools and approaches, and is cost-and time-effective. There is currently no other biological research on dementia at UTEP. Dementia prevalence is disproportionately higher in Hispanics than white Americans thus this study will not only promote research relevant to our students and community but also increase the representation of Hispanics in neuroscience research that is disproportionately low at present.

项目摘要 本研究的主要目标是确定具有功能意义的遗传风险因素 模式生物果蝇中的痴呆。痴呆症的关键因素是年龄 依赖性神经变性削弱执行功能（例如抑制控制）和 记忆。大多数痴呆症研究都集中在记忆丧失上，这是痴呆症的一个突出症状 AD——最常见的痴呆类型。虽然动物模型提供了重要的见解 记忆丧失的机制，自该研究以来，它们在痴呆基因发现中的效用有限 记忆力减退是一件费时又费力的事情。执行缺陷是早期的主要症状 AD 阶段和相关痴呆症尚未得到充分研究。我们通过以下方式克服这些限制 研究抑制控制缺陷作为痴呆的内表型以发现痴呆 基因，创新。我们的方法是对遗传位点进行公正的筛选 以年龄依赖性方式导致功能失调的抑制控制，无论有或没有非 遗传风险因素。在这个提案中，我们还将检验遗传和非遗传性的假设 遗传风险因素相互作用对痴呆症的影响比单独的遗传因素更大。 果蝇易于处理学生研究培训和教育，因为它易于处理，允许 轻松应用最先进的工具和方法，并且具有成本效益和时间效益。有 目前 UTEP 没有其他关于痴呆症的生物学研究。痴呆症患病率是 西班牙裔美国人的比例不成比例地高于美国白人，因此这项研究不仅会促进 与我们的学生和社区相关的研究，同时也增加了西班牙裔的代表性 目前神经科学研究的水平极低。