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和发展的原因和发展 神经退行性疾病和疾病的治疗，特别是阿尔茨海默氏症 疾病（AD）和多发性硬化症（MS）。 FDA批准了其他适应症，但我们表明可以在动物模型中提供好处 广告和MS，使诊所更容易理解。 这些疾病开始和发展，并识别国际 疾病症状以及社会和经济负担。 由绩效赠款资助已扩展到可能的遗传因素领域 根据我们对新型核苷酸变体的发现，易于发展MS。 一个特定的基因。 我们开发的培养物和小鼠模型，以复制人类变体和测试 吸毒是否可以最小化是效果。 在某些退伍军人人口中以更高的自由定位，包括非洲 美国，西班牙裔和高加索人同时。 全国MS协会，我们正在测试MS鼠标中的一种新颖化合物 相信会减少神经元损伤，并增加周围的髓鞘 和保护神经细胞。 我们还在研究一个项目来评估奉献精神的酒精 关于AD的开发的消费。 细胞）乙醇降低了它们清除淀粉样蛋白的能力； 对AD的小鼠模型的细胞研究。 可能对我们的活跃军队以及退伍军人人口特别重要， 即研究可能由常用抗抗的神经系统损害 凝结剂（例如Warfarin），以及用作用作的更有效的“ Superwarfarins” 我们是啮齿动物，但不幸的是，也已用于军事现场。 使用FDA批准的药物开发方法，我们希望可以防止 这些药物以及长期后果。