BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10047240
• 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/10047240
• 关键词: Affect; African American; 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; Hispanics; 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; prevent; recruit; reduce symptoms; 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其原因和发展 神经退行性疾病和病症的治疗，特别是阿尔茨海默病 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，但我们证明可以在动物模型中提供益处 AD 和 MS，让他们更容易去诊所。更好地理解如何 这些疾病的发生和发展，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。我们目前的硕士研究 由优异奖资助的项目已扩展到可能的遗传风险因素领域 根据我们对一种新的核苷酸变异的发现，人们容易患上多发性硬化症 一个特定的基因。我们现在正在使用细胞确定该变体如何增加风险 我们开发了用于复制人类变异的培养物和小鼠模型，并进行了测试 药物，看看是否可以最大限度地减少其影响。我们还在测试这个变体或其他变体是否 在某些退伍军人群体中出现的频率较高，包括在非洲 美国人、西班牙裔和白人群体。同时，在由 国家多发性硬化症协会，我们正在多发性硬化症小鼠模型中测试一种新型化合物 相信会减少神经元损伤并增加周围的髓鞘 并保护神经细胞。 我们还在开展一个项目来评估过量饮酒的后果 消费对AD发展的影响。我们发现暴露大脑“支持”细胞（胶质细胞 细胞）乙醇会降低其清除淀粉样斑块的能力；我们计划延长这些 AD 小鼠模型的细胞研究。我们还获得资助进行研究 可能对我们现役军人和退伍军人特别重要， 即对常用抗药物可能引起的神经损伤的研究 凝血剂（例如华法林），以及更有效的“超级华法林”，用作 灭鼠剂，但不幸的是也被用于军事场合。我们是 使用 FDA 批准的药物开发方法，我们希望能够防止毒性作用 这些药物以及长期后果。