BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10293581
• 负责人: Douglas L. Feinstein
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293581
• 关键词: Affect; African American; African American population; Age; Aging; Agonist; Alcohol abuse; Alcohol consumption; Alcohols; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Anticoagulants; Area; Award; Behavior; Blood specimen; Brain; Calcium; Caucasians; Cell Culture Techniques; Cells; Clinic; Clinical; Clinical Trials; Cognitive deficits; Craniocerebral Trauma; DNA; DNA sequencing; Deposition; Development; Developmental Therapeutics Program; Diagnosis; Dietary Factors; Disease; Down-Regulation; Economic Burden; Environmental Risk Factor; Ethanol; Experimental Autoimmune Encephalomyelitis; Exposure to; FDA approved; Family; Frequencies; Funding; Genes; Genetic; Goals; Grant; Healthcare Systems; Heavy Drinking; High Prevalence; Hispanic; Human; In Vitro; Incidence; Inflammation; Inflammatory Response; Intervention; Knowledge; LAMC2 gene; Lesion; Mediating; Metformin; Methods; Microglia; Military Personnel; Modeling; Multiple Sclerosis; Myelin Sheath; Nervous System Trauma; Neurobiology; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Neurosciences; Nitric Oxide Synthase; Norepinephrine; Nucleotides; Paper; Pathology; Patients; Phagocytosis; Pharmaceutical Preparations; Pilot Projects; Pioglitazone; Population; Post-Traumatic Stress Disorders; Protein-Serine-Threonine Kinases; Proteins; Rattus; Relapsing-Remitting Multiple Sclerosis; Research; Risk; Risk Factors; Rodent Model; Rodenticides; Role; STK11 gene; Sampling; Scientist; Seminal; Senile Plaques; Services; Severities; Siblings; Signal Transduction; Single Nucleotide Polymorphism; Societies; Supporting Cell; Symptoms; Syndrome; System; T-Lymphocyte; Testing; Time; Toxic effect; Variant; Veterans; Warfarin; Woman; Work; alcohol effect; base; career; cohort; comorbidity; design; disorder risk; drug repurposing; drug testing; genetic risk factor; in vivo; interest; locus ceruleus structure; military veteran; mouse model; multiple sclerosis patient; neuroinflammation; neuropathology; noradrenergic; novel; phase I trial; pilot test; prevent; recruit; reduce symptoms; remyelination; social; therapy development; transcriptome; β-amyloid burden

The major area of our research is to help understand the causes of, and development treatments for neurodegenerative diseases and conditions, in particular Alzheimer’s Disease (AD) and Multiple Sclerosis (MS). This work includes repurposing drugs that are FDA-approved for other indications but we show can provide benefit in animal models of AD and MS, making it easier to bring them to the clinic. A better understanding of how these diseases start and evolve, and identification of interventions will help reduce disease symptoms, as well as social and economic burdens. Our MS studies currently funded by a Merit grant have expanded into the area of genetic risk factors that may predispose one to developing MS, based on our findings of a novel nucleotide variant in one particular gene. We are now determining how the variant increases risk using cell cultures and a mouse model that we developed to replicate the human variant, and testing drugs to see if they can minimize its effects. We are also testing if this variant, or others, is present at higher frequency in certain veteran populations, including in African American, Hispanic, and Caucasian cohorts. At the same time in work funded by the National MS society, we are testing a novel compound in a mouse model of MS we believe will reduce neuronal damage and also increase the myelin sheath that surrounds and protections nerve cells. We are also working on a project to evaluate the consequences of excessive alcohol consumption on the development of AD. We found that exposing brain ‘support’ cells (glial cells) to ethanol reduces their ability to clear amyloid plaques; we plan to extend those cell studies to a mouse model of AD. We have also been funded to carry out studies that may have particular importance to our active military as well as veteran population, namely studies on possible neurological damage caused by commonly used anti- coagulants (e.g.warfarin), and also more potent ‘superwarfarins’ that are used as rodenticides, but unfortunately have also been used in military situations. We are developing methods using FDA-approved drugs, we hope will prevent the toxic effects of these drugs as well as long term consequences.

我们研究的主要领域是帮助了解的原因， 用于神经变性疾病和病症，特别是阿尔茨海默氏病的治疗 疾病（AD）和多发性硬化症（MS）。这项工作包括重新利用药物， FDA批准用于其他适应症，但我们显示可以在动物模型中提供益处， AD和MS，使其更容易把他们带到诊所。更好地了解如何 这些疾病的开始和发展，确定干预措施将有助于减少 疾病症状，以及社会和经济负担。目前，MS研究 由优异奖助金资助的研究已经扩展到遗传风险因素领域， 易患MS，基于我们对MS中一种新的核苷酸变异的发现， 一个特定的基因。我们现在正在确定变异如何增加风险使用细胞 我们开发了一种小鼠模型来复制人类的变异， 看看他们是否能将其影响降到最低。我们也在测试这个变种，或者其他变种， 在某些退伍军人群体中，包括在非洲， 美国人，西班牙人，和高加索人队列。与此同时， 国家多发性硬化症协会，我们正在测试一种新的化合物在小鼠模型的多发性硬化症， 相信这将减少神经元损伤，并增加髓鞘周围的 保护神经细胞。 我们还在开展一个项目，评估过量饮酒的后果 消费对AD的发展。我们发现暴露的大脑“支持”细胞（神经胶质细胞） 细胞）对乙醇的吸收会降低它们清除淀粉样斑块的能力;我们计划延长这些能力， 对AD小鼠模型的细胞研究。我们还得到资助进行研究， 可能对我们的现役军人和退伍军人特别重要， 即对常用抗病毒药物可能引起的神经损伤的研究 凝血剂（如华法林），以及更有效的“超级华法林”， 灭鼠剂，但不幸的是，也被用于军事情况。我们 开发使用FDA批准的药物的方法，我们希望能防止 这些药物以及长期的后果。