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.

与年龄相关的神经疾病是我们社会的一个重大且日益沉重的负担。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)，现实是几乎所有的神经退行性疾病病例都具有混合性成分 病理学。被诊断为阿尔茨海默病的人通常具有与其他人相同的神经病理特征 疾病。例如，tau病理也在某些形式的额颞叶痴呆、肌萎缩侧索硬化症和其他疾病中发现。 神经退行性疾病的一种形式，也被认为是神经病理学的一种关键形式 在创伤性脑损伤之后。脑血管疾病(CVD)在有脑血管疾病病史的个体中大量存在 肥胖(和2型糖尿病，或T2D)，众所周知，这会增加患痴呆症的风险。总体而言，它是 事实上，很少发现缺乏脑血管共病病理因素的AD病例。目前还不清楚 至于这些病理因素是否以相加或协同的方式导致痴呆症。在……里面 最近在我们实验室的研究中，我们观察到了有趣的关系，在不同方面 可能与阿尔茨海默病和心血管疾病有关的神经病理学。我们已经确定了一种膜离子交换器， NHE1(SLC9A1)，可能参与这两个病理过程。NHE1已被证明参与其中 神经损伤和tau病理，正如我们的初步数据所示。这个项目试图确定 这种交换器的功能是否对这两种病理中的一种或两种都重要。这个项目 结合遗传学和药理学方法来探索这一令人兴奋的新靶点 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。在特定目标中1 (SA1)，我们将在一个独特的小鼠模型中研究膜离子交换NHE1的机制。 结合AD和CVD相关的病理，使用高度特异的药理学试剂。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病理的形成。 NHE1基因减少的背景。疗效将通过一系列免疫组织化学来确定， 病理的分子和生化标记物，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的多个方面的病理，以及 干预其活动将改善这些问题，并将缓解认知功能障碍。这是一个 高度创新的假说，据我们所知，以前从未被探索过。这方面的另一种力量 方案是使用了一种具有独特功能的新颖鼠标模型。这个项目有能力显著地 提高我们对共病神经病理的理解，并可能对 治疗和预防与年龄相关的神经退行性疾病。