SLC9A1 and Neurodegenerative Disease

SLC9A1 与神经退行性疾病

基本信息

批准号：
9898214
负责人：
ADAM D BACHSTETTER
金额：
$ 19.13万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2019-04-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898214
关键词：
Acute Address Affect Age-Months Albumins Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Amyloid Amyloid beta-42 Animal Model Attenuated Biochemical Markers Blood Vessels CD34 gene Cerebrovascular Disorders Cytoskeleton Data Dementia Development Diagnosis Diet Disease Disease model Elements Ensure Experimental Designs Extravasation Frontotemporal Dementia Future Genes Genetic Glial Fibrillary Acidic Protein Gliosis Human Immunoglobulin G Impaired cognition Individual Ions Knowledge Late Onset Alzheimer Disease Link Magnetic Resonance Imaging Mediating Membrane Modeling Mus NHE1 Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Injury Non-Insulin-Dependent Diabetes Mellitus Obesity PHF-1 Palliative Care Pathologic Pathologic Processes Pathology Pathway interactions Pharmacology Prevention Prussian blue PubMed Recording of previous events Research Risk Role Societies Therapeutic Trauma Traumatic Brain Injury VWF gene Vascular Diseases Vascular remodeling Viral Virus Work age related age related neurodegeneration axon injury base cerebrovascular cerebrovascular pathology cognitive function comorbidity cresyl violet dementia risk immunohistochemical markers improved innovation insight ischemic injury mixed dementia molecular marker morris water maze mouse model nervous system disorder neuron loss neuropathology novel preclinical study prevent primary endpoint small molecule inhibitor stroke model tau Proteins therapeutic target vascular cognitive impairment and dementia vascular injury vector control virtual

项目摘要

Age-related neurologic disease is a significant and growing burden on our society. Although the largest share of research effort has typically been devoted to the common neurodegenerative illnesses (such as Alzheimer's disease, or AD), the reality is that nearly all cases of neurodegenerative disease possess elements of mixed pathology. Individuals diagnosed with AD frequently harbor neuropathologic hallmarks common in other diseases. For example, tau pathology is also found in some forms of frontotemporal dementia, ALS, and other forms of neurodegenerative disease, and is also believed to be a key form of neuropathology that develops following traumatic brain injury. Cerebrovascular disease (CVD) is abundant in individuals with a history of obesity (and type 2 diabetes, or T2D), which have a well known elevated risk of dementia. In general, it is actually quite rare to identify AD cases lacking elements of co-morbid cerebrovascular pathology. It is unclear as to whether these elements of pathology contribute to dementia in an additive or synergistic manner. In recent studies in our lab, we have observed an intriguing relationship between various aspects of neuropathology that could potentially connect to AD and CVD. We have identified a membrane ion exchanger, NHE1 (SLC9A1), as potentially involved in both pathologic processes. NHE1 has been shown to be involved with neuronal injury, and tau pathology as our preliminary data indicates. This project seeks to determine whether the function of this exchanger is important for either, or both, of these pathologies. This project combines both genetic and pharmacologic approaches to explore this exciting new target that has not previously been examined as a major player in age-related neurodegenerative disease. In specific aim 1 (SA1), we will investigate the mechanism of the membrane ion exchanger NHE1 in a unique mouse model combining AD- and CVD-related pathology, using a highly specific pharmacologic agent. In SA2, we will investigate how this membrane ion exchanger drives the formation of tau pathology, by over expressing tau on a background of NHE1 genetic reduction. Efficacy will be determined using a range of immunohistochemical, molecular, and biochemical markers of pathology, as well as gauging changes in cognitive function. We hypothesize that NHE1 will be responsible for multiple aspects of neurodegenerative disease pathology, and that interfering with its activity will ameliorate these problems, and will alleviate cognitive dysfunction. This is a highly innovative hypothesis that, to our knowledge, has not been previously explored. Another strength of this proposal is the use of a novel mouse model with unique features. This project has the capacity to significantly improve our understanding of co-morbid neuropathologies, and could have significant implications for the treatment and prevention of age-related neurodegenerative disease.

与年龄相关的神经系统疾病是我们社会的一个重大且日益严重的负担。虽然份额最大的研究工作通常致力于常见的神经退行性疾病（例如阿尔茨海默病）疾病，或 AD），现实是几乎所有神经退行性疾病病例都具有混合的要素病理。被诊断患有 AD 的个体经常具有其他疾病中常见的神经病理学特征疾病。例如，tau 蛋白病理学也存在于某些形式的额颞叶痴呆、ALS 和其他疾病中。神经退行性疾病的一种形式，也被认为是神经病理学发展的一种关键形式脑外伤后。脑血管疾病（CVD）在有以下病史的个体中很常见：众所周知，肥胖（以及 2 型糖尿病或 T2D）会增加患痴呆症的风险。一般来说，是事实上，很难识别出缺乏共病脑血管病理因素的 AD 病例。目前还不清楚这些病理因素是否以相加或协同的方式导致痴呆。在在我们实验室最近的研究中，我们观察到各个方面之间存在着有趣的关系可能与 AD 和 CVD 相关的神经病理学。我们已经确定了一种膜离子交换器， NHE1 (SLC9A1)，可能参与这两种病理过程。 NHE1已被证明参与其中正如我们的初步数据所示，与神经元损伤和 tau 蛋白病理学有关。该项目旨在确定该交换器的功能对于这些病理中的一种或两种是否重要。这个项目结合遗传和药理学方法来探索这个令人兴奋的新目标，之前被检查为与年龄相关的神经退行性疾病的主要参与者。具体目标1 (SA1)，我们将在独特的小鼠模型中研究膜离子交换器NHE1的机制结合 AD 和 CVD 相关病理学，使用高度特异性的药物。在 SA2 中，我们将研究这种膜离子交换器如何通过过度表达 tau 来驱动 tau 病理学的形成 NHE1基因减少的背景。将使用一系列免疫组织化学方法来确定功效，病理学的分子和生化标记，以及测量认知功能的变化。我们假设 NHE1 将负责神经退行性疾病病理学的多个方面，并且干扰其活动将改善这些问题，并减轻认知功能障碍。这是一个据我们所知，以前从未探索过这一高度创新的假设。这的另一个优点提案是使用具有独特功能的新型小鼠模型。该项目有能力显着提高我们对共病神经病理学的理解，并可能对治疗和预防与年龄相关的神经退行性疾病。