SLC9A1 and Neurodegenerative Disease

SLC9A1 与神经退行性疾病

• 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
• 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' s Disease; Alzheimer' s disease pathology; Alzheimer' 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

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.

脑卒中相关的神经系统疾病是我们社会的一个重大和日益增长的负担。虽然最大的份额 的研究工作通常致力于常见的神经退行性疾病（如阿尔茨海默氏症 疾病，或AD），现实情况是，几乎所有的神经退行性疾病的情况下，具有混合的元素 病理被诊断患有AD的个体经常具有在其他疾病中常见的神经病理学特征。 疾病例如，在额颞叶痴呆、ALS和其他痴呆的一些形式中也发现了tau病理学。 神经退行性疾病的形式，也被认为是神经病理学的一种关键形式， 脑外伤后死亡脑血管疾病（CVD）在有以下病史的个体中大量存在： 肥胖症（和2型糖尿病，或T2D），这是众所周知的痴呆症风险升高。总的来说是 事实上，识别缺乏共病脑血管病理学要素的AD病例非常罕见。目前还不清楚 这些病理因素是否以叠加或协同的方式导致痴呆。在 在我们实验室最近的研究中，我们观察到了一个有趣的关系， 可能与AD和CVD有关的神经病理学我们发现了一种膜离子交换器， NHE1（SLC9A1）可能参与两种病理过程。NHE1已被证明参与 神经元损伤和tau蛋白病理学。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 结合遗传学和药理学方法来探索这个令人兴奋的新靶点， 以前被认为是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)我们将在一个独特的小鼠模型中研究膜离子交换剂NHE 1的作用机制。 结合AD和CVD相关的病理学，使用高度特异性的药理学试剂。在SA2中，我们将 研究这种膜离子交换剂如何通过在细胞表面过度表达tau蛋白来驱动tau病理的形成， NHE1基因减少的背景。将使用一系列免疫组织化学， 病理学的分子和生化标志物，以及认知功能的测量变化。我们 假设NHE 1将负责神经变性疾病病理学多个方面， 干扰它的活动将改善这些问题，并将减轻认知功能障碍。这是一 据我们所知，这是一个高度创新的假设，以前没有被探索过。另一个优点是 建议是使用一种具有独特功能的新型小鼠模型。该项目具有显著的 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。