BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10451498
• 负责人: MARK S. KINDY
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451498
• 关键词: Advanced Glycosylation End Products; Affect; Afghanistan; Age; Age-Years; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloidosis; Animals; Antibodies; Antigens; Antisense Oligonucleotides; Apolipoprotein E; Apoptotic; Area; Attention; Autopsy; Award; Beer; Binding; Blood; Blood Vessels; Boston; Brain; Brain Concussion; Budgets; C9ORF72; CASP1 gene; Cardiovascular Diseases; Cardiovascular Physiology; Cathepsins B; Cell Death; Cerebral Ischemia; Chronic Disease; Chronic Kidney Failure; Clinic; Clinical; Clinical Sciences; Collaborations; Common Acute Lymphoblastic Leukemia; Complement; Complications of Diabetes Mellitus; Diabetes Mellitus; Disease; Disease model; Doctor of Philosophy; FGFR4 gene; Family; Florida; Functional disorder; Gene Activation; General Population; Generations; Genes; Goals; Grant; Health; Healthcare; High Fat Diet; Huntington Disease; Hydrophobicity; Hyperlipidemia; Impaired cognition; Inflammasome; Inflammation; Inflammatory; Injury; Interleukin-1; Iraq; Journals; Left Ventricular Hypertrophy; Length; Lentivirus Vector; Ligands; Liver; Low Density Lipoprotein Receptor; Maintenance; Mediating; Medical center; Memory Loss; Metabolic Diseases; Metabolic syndrome; Metalloproteases; Modeling; Mus; Natural Immunity; Nature; Neprilysin; Neurodegenerative Disorders; Neurologic; Neurological outcome; Obesity; Outcome; Oxides; Paper; Parkinson Disease; Pathogenesis; Pathologic Processes; Pathway interactions; Peer Review; Peptides; Pharmacologic Substance; Pharmacy facility; Phospholipids; Play; Population; Post-Traumatic Stress Disorders; Process; Production; Protein Isoforms; Proteins; Publishing; Rattus; Reactive Oxygen Species; Reagent; Recovery; Research; Risk; Risk Factors; Rodent Model; Role; Science; Scientist; Senile Plaques; Serum Amyloid P-Component; Serum amyloid A protein; Side; Signal Pathway; Signal Transduction; Sodium Chloride; Spinal cord injury; Stroke; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Animals; Transgenic Organisms; Translating; Trauma; Traumatic Brain Injury; Universities; Veterans; Virus Inhibitors; Vitamin D; Work; Zinc; aged; amyloid formation; amyloidogenesis; career; chronic traumatic encephalopathy; cognitive function; college; cytokine; design; direct application; health disparity; human disease; immunoglobulin receptor; improved; in vivo; indexing; inhibitor; interest; islet amyloid polypeptide; knockout gene; learning ability; military veteran; mouse model; nervous system disorder; neuroinflammation; neuromuscular; neuron loss; new therapeutic target; novel; overexpression; professor; programs; protein TDP-43; receptor; receptor for advanced glycation endproducts; relating to nervous system; small molecule inhibitor; soluble RAGE; stroke model; stroke outcome; superoxide dismutase 1; synuclein; tau Proteins; therapeutic development; tumor

The PI, Mark S. Kindy, Ph.D., has been studying the mechanisms and pathways associated with a number of neurological and neurodegenerative disorders. These include, Alzheimer’s disease (AD), stroke, Parkinson’s disease (PD), traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), spinal cord injury (SCI), among others. All of these disorders are afflictions that are present in the VA population and contribute significantly to the overall health of the Veterans. The overarching goal is to understand the mechanisms involved in the disease processes and to develop therapeutic approaches to treat them. I have three basic areas of research that we focus on. The first program is centered around stroke and the impact of negative vascular health factors (such as: obesity, diabetes, age, salt sensitivity hyperlipidemia, and hypertensivity) on the induction of reactive oxygen species (ROS) production and activation of the inflammation (inflammasome). We have shown that aged animals with the risk factors have worse outcomes and recovery is exacerbated due to the presence of both systemic and neuroinflammation. The generation of better clinical models of stroke to test these risk factors and health disparities following injury. Studies using low-density lipoprotein receptor (ldlr) deficient mice with and without high fat diet are being used to study the impact of oxidized phospholipids (OxPLs) on stroke outcomes. Mice expressing OxPL antibodies will be tested for protection from stroke. Finally, we are examining the impact of chronic kidney disease, left ventricular hypertrophy and FGF23 on stroke and stroke outcomes. Mice with targeted deletion of the fgfr4 gene or overexpression of the FGF23 are being examined for stroke outcomes. These studies will better capture the true nature of veterans and civilians who have a stroke and provide a better approach to treating the disease. A second line of research focuses on the role of serum amyloid A (SAA) proteins in the pathogenesis of stroke. Recent studies have implicated SAAs in innate immunity and various disorders, however the precise mechanism eludes us. SAAs are elevated following stroke (cerebral ischemia) and TBI, and our studies show that SAA increases the cytokine interleukin-1 (IL-1), which is mediated by Nod-like receptor protein 3 (NLRP3) inflammasome, cathepsin B and caspase-1 and may play a role in the pathogenesis of neurological disorders. Using transgenic and gene deleted mice as well as AAV expressing constructs we are evaluating the impact of SAA on stroke and other neurological diseases. Another line of research focuses on serum amyloid P component (SAP), which is found in all amyloids and studies have suggested that it plays an integral role in the formation, progression, and maintenance of the amyloid disease processes. The amyloid diseases include: AD, PD (tau, -synuclein, TDP-43), tauopathies, CTE, ALS (SOD1, TDP-43, C9ORF72), systemic amyloids (AA, TTR, amylin), Huntington’s disease (HD), ABri and ADan. Inflammation modifies SAP function, and inflammatory signaling pathways impair cognitive function in vivo. Our long-term goal is to determine the mechanisms regulating SAP function, particularly within the setting of AD and inflammatory diseases. Consequently, the objective of this grant is to characterize the role for SAP in inflammation and AD. We have developed and amassed various transgenic and gene deleted mice as well as viruses and inhibitors to determine the impact of SAP in the amyloid diseases. Since both SAA and SAP are produced mainly in the liver, we are working with Ionis Pharmaceuticals in the design and testing of antisense oligonucleotides (ASOs) as therapeutic approaches to these disorders. In addition, we are working with clinicians at the Haley VA and other VAs (Boston CTE Center) and Universities around the US to correlate the animal studies with human disease. Using autopsy tissues, blood, CSF and other reagents to validate the studies in our mouse and rat models. This is critical to our basic understanding of the disease process and in the development of therapeutics for treatment.

PI Mark S. Kindy 博士一直在研究与许多相关的机制和途径 神经系统和神经退行性疾病。其中包括阿尔茨海默病 (AD)、中风、帕金森病 疾病（PD）、创伤性脑损伤（TBI）、慢性创伤性脑病（CTE）、脊髓损伤（SCI）、 除其他外。所有这些疾病都是退伍军人群体中存在的痛苦，并导致 对退伍军人的整体健康有显着影响。首要目标是了解机制 参与疾病过程并开发治疗方法。我有三个基本领域 我们关注的研究。第一个项目以中风和负面血管的影响为中心 健康因素（如：肥胖、糖尿病、年龄、盐敏感性、高脂血症、高血压）对 诱导活性氧 (ROS) 产生和炎症激活（炎症小体）。我们 已经表明，具有危险因素的老年动物的结果更差，并且由于以下原因而导致恢复加剧 全身炎症和神经炎症的存在。生成更好的中风临床模型进行测试 这些危险因素和受伤后的健康差异。使用低密度脂蛋白受体 (ldlr) 的研究 有或没有高脂肪饮食的缺陷小鼠被用来研究氧化磷脂 (OxPL) 的影响 关于中风结果。将测试表达 OxPL 抗体的小鼠是否能预防中风。最后，我们是 检查慢性肾病、左心室肥厚和 FGF23 对中风和中风的影响 结果。正在检查 fgfr4 基因定向缺失或 FGF23 过度表达的小鼠 中风结果。这些研究将更好地了解中风退伍军人和平民的真实本质 并提供更好的治疗该疾病的方法。第二条研究重点是血清的作用 淀粉样蛋白 A (SAA) 蛋白在中风发病机制中的作用。最近的研究表明 SAA 与先天免疫有关 和各种疾病，但确切的机制我们却不清楚。中风后 SAA 升高（脑卒中） 缺血）和 TBI，我们的研究表明 SAA 会增加细胞因子白细胞介素 1 (IL-1)，这是 由 Nod 样受体蛋白 3 (NLRP3) 炎性体、组织蛋白酶 B 和 caspase-1 介导，可能发挥 在神经系统疾病的发病机制中的作用。使用转基因和基因删除小鼠以及 AAV 我们正在评估 SAA 对中风和其他神经系统疾病的影响。其他 研究方向集中于血清淀粉样蛋白 P 成分 (SAP)，它存在于所有淀粉样蛋白中，并且有研究表明 表明它在淀粉样蛋白疾病的形成、进展和维持中起着不可或缺的作用 流程。淀粉样蛋白疾病包括：AD、PD（tau、α-突触核蛋白、TDP-43）、tau蛋白病、CTE、ALS（SOD1、 TDP-43、C9ORF72)、系统性淀粉样蛋白（AA、TTR、胰淀素）、亨廷顿病 (HD)、ABri 和 ADan。 炎症改变 SAP 功能，炎症信号通路损害体内认知功能。我们的 长期目标是确定调节 SAP 功能的机制，特别是在 AD 和 炎症性疾病。因此，这笔赠款的目的是描述 SAP 在以下方面的作用： 炎症和AD。我们开发并积累了各种转基因和基因缺失小鼠以及 病毒和抑制剂以确定 SAP 在淀粉样蛋白疾病中的影响。由于 SAA 和 SAP 都是 主要在肝脏中产生，我们正在与 Ionis Pharmaceuticals 合作设计和测试反义药物 寡核苷酸（ASO）作为这些疾病的治疗方法。此外，我们正在与 Haley VA 和其他 VA（波士顿 CTE 中心）以及美国各地大学的临床医生将 人类疾病的动物研究。使用尸检组织、血液、脑脊液和其他试剂来验证研究 在我们的小鼠和大鼠模型中。这对于我们对疾病过程和疾病的基本了解至关重要 开发治疗方法。