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Olfactory Epithelium Responses to Human APOE Alleles

嗅觉上皮对人类 APOE 等位基因的反应

基本信息

批准号：
10659303
负责人：
Timothy S McClintock
金额：
$ 22.95万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659303
关键词：
Adult Affect Age Alleles Alzheimer associated neurodegeneration Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Apolipoprotein E Autopsy Biopsy Blood - brain barrier anatomy Brain Cells Central Nervous System Characteristics Chronic Complex Data Data Correlations Development Diagnosis Disease Disease Progression Disease model Early identification Epithelium Event Foundations Gene Expression Genetic Genetic Models Genotype Glucose Goals Human Human Amyloid Precursor Protein Immune response Individual Intervention Late Onset Alzheimer Disease Learning Link MAPT gene Measures Messenger RNA Metabolic dysfunction Microglia Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Olfactory Epithelium Olfactory Pathways Outcome Pathologic Pathway interactions Persons Pharmaceutical Preparations Phenotype Predisposition Probability Proxy Publishing Regenerative capacity Research Risk Factors Risk Reduction Site Smell Perception Stress Supporting Cell Symptoms Testing Tissues Work age effect age related apolipoprotein E-3 apolipoprotein E-4 cell type experimental study gene therapy genetic manipulation genetic variant glucose uptake improved in vivo in vivo Model lipidome middle age mouse model mutant neural neuroinflammation neuron apoptosis neuronal survival neuroprotection novel olfactory sensory neurons prevent protective effect response single-cell RNA sequencing slow axonal transport success sustentacular cell synergism therapy design transcriptome young adult

项目摘要

Project Summary: Deficits in olfaction were recognized decades ago as early symptoms in people with incipient Alzheimer’s Disease. However, these discoveries have had less impact than hoped on the study, diagnosis, and treatment of this disease. Though central nervous system olfactory pathways suffer the plaques and/or tangles that are characteristic of late-stage disease, these symptoms do not set the olfactory system apart from other foci of research into Alzheimer’s Disease. Perhaps because the regenerative capacity of the olfactory epithelium obscured the vulnerability of olfactory sensory neurons to Alzheimer’s Disease, especially the early events leading to the neurodegeneration characteristic of the disease, study of how the olfactory epithelium is impacted by Alzheimer’s Disease languished. Clear evidence that the olfactory sensory neurons in the epithelium are susceptible to factors that cause or increase risk of Alzheimer’s Disease has recently emerged, however. These findings demonstrate that the olfactory epithelium is a worthy model of how risk factors for Alzheimer’s Disease affect neurons and their supporting cells. Thus far the data correlate well with effects in the brain, evidence that the olfactory epithelium may be a bellwether for events transpiring in the central nervous system. The accessibility of the olfactory epithelium for biopsy to assess disease progression in individuals and to drugs that cannot pass the blood brain barrier further elevates the significance of the olfactory epithelium as a model. This project investigates the effects of a critical risk factor for Alzheimer’s Disease, APOE genotype, on the olfactory epithelium and its olfactory sensory neurons. The experiments focus on identifying early events and the strength of their effects on phenotype and function. It uses mouse models of the disease, including established genetic models previously used to investigate effects in the brain and a novel model that allows switching at will from a neurodegenerative genotype to a neuroprotective genotype. The latter allows testing of whether cellular and molecular events associated with vulnerability to Alzheimer’s Disease can be prevented or reversed by in vivo genetic manipulation, outcomes that would inform and inspire further work towards curing this disease.

项目概要：嗅觉缺陷在几十年前就被认为是早期阿尔茨海默氏症患者的早期症状疾病然而，这些发现对研究，诊断和治疗的影响比希望的要小这种疾病。尽管中枢神经系统的嗅觉通路遭受斑块和/或缠结，作为晚期疾病的特征，这些症状不会将嗅觉系统与其他病灶分开，阿尔茨海默病的研究也许是因为嗅觉上皮的再生能力模糊了嗅觉感觉神经元对阿尔茨海默病的脆弱性，特别是早期事件，导致疾病的神经变性特征，研究嗅觉上皮是如何受老年痴呆症影响的人明确的证据表明，嗅觉感觉神经元在上皮细胞易受导致或增加阿尔茨海默病风险的因素的影响最近出现，然而.这些发现表明，嗅上皮是一个有价值的模型，如何风险因素，阿尔茨海默病影响神经元及其支持细胞。到目前为止，这些数据与以下方面的影响相关性很好：大脑，证据表明嗅觉上皮可能是中央事件的领头羊神经系统嗅上皮活检评估疾病进展的可及性个体和不能通过血脑屏障的药物进一步提高了嗅上皮作为模型。该项目调查了阿尔茨海默氏症的一个关键风险因素的影响疾病，APOE基因型，嗅觉上皮及其嗅觉感觉神经元。实验重点是识别早期事件及其对表型和功能影响的强度。它使用鼠标疾病的模型，包括以前用于研究大脑影响的已建立的遗传模型以及一种允许随意从神经退行性基因型切换到神经保护性基因型的新型模型基因型后者允许测试细胞和分子事件是否与易感性相关，阿尔茨海默病可以通过体内遗传操作来预防或逆转，结果将告知并激发进一步的工作来治愈这种疾病。