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：几十年前，嗅觉缺陷就被认为是阿尔茨海默病初期患者的早期症状然而，这些发现对研究、诊断和治疗的影响并不如预期。尽管中枢神经系统嗅觉通路受到斑块和/或缠结的影响。作为晚期疾病的特征，这些症状并不会将嗅觉系统与其他疾病灶区分开来。也许是因为嗅觉上皮的再生能力。掩盖了嗅觉感觉神经元对阿尔茨海默病的脆弱性，尤其是早期事件导致该疾病的神经变性特征，研究嗅觉上皮如何明显的证据表明，大脑中的嗅觉感觉神经元受到阿尔茨海默病的影响。上皮细胞容易受到最近出现的导致或增加阿尔茨海默病风险的因素的影响，然而，这些研究结果表明，嗅觉上皮是一个有价值的模型，可以用来解释危险因素的作用。迄今为止，阿尔茨海默病影响神经元及其支持细胞。大脑，有证据表明嗅觉上皮可能是中枢发生事件的风向标嗅觉上皮的可及性用于活检以评估疾病进展。个人和无法通过血脑屏障的药物进一步提升了该项目研究了阿尔茨海默病的一个关键危险因素的影响。疾病，APOE 基因型，对嗅觉上皮及其嗅觉感觉神经元的实验。专注于识别早期事件及其对表型和功能的影响强度它使用小鼠。该疾病的模型，包括先前用于研究大脑影响的已建立的遗传模型以及一种新的模型，可以随意从神经退行性基因型切换到神经保护性基因型后者可以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基因操作来预防或逆转，结果将告知并进一步激发治愈这种疾病的工作。