BLRD Research Career Scientist Award Application

PI，Mark S。Kindy博士，一直在研究与许多疾病相关的机制和途径， 神经和神经变性疾病。这些疾病包括阿尔茨海默氏病（AD）、中风、帕金森氏病、中风等。 疾病（PD）、创伤性脑损伤（TBI）、慢性创伤性脑病（CTE）、脊髓损伤（SCI）， 还有其他的所有这些疾病都是VA人群中存在的痛苦， 这对退伍军人的整体健康至关重要。首要目标是了解 参与疾病过程，并开发治疗方法来治疗它们。我有三个基本领域 第一个项目是围绕中风和负血管效应的影响， 健康因素（如：肥胖、糖尿病、年龄、盐敏感性高脂血症和高血压）对 诱导活性氧（ROS）产生和激活炎症（炎性小体）。我们 已经表明，具有风险因素的老年动物的结果更糟，并且由于以下原因而加剧了恢复 全身和神经炎症的存在。产生更好的中风临床模型来测试 这些风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 有和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， 中风的结果。将测试表达OxPL抗体的小鼠对中风的保护。最后，我们 研究慢性肾脏疾病、左心室肥大和FGF 23对中风和中风的影响 结果。对具有fgfr 4基因靶向缺失或FGF 23过表达的小鼠进行检查， 卒中结局。这些研究将更好地捕捉退伍军人和平民谁中风的真实性质 并提供一种更好的治疗方法。第二条研究线集中在血清的作用 淀粉样蛋白A（SAA）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 以及各种疾病，然而我们却不知道其确切的机制中风后SAA升高（脑卒中） 我们的研究表明SAA增加了细胞因子白细胞介素-1 β（IL-1 β）， Nod-like receptor protein 3（NLRP 3）inflammasome，cathepsin B and caspase-1介导的炎症反应， 在神经系统疾病发病机制中的作用。使用转基因和基因缺失小鼠以及AAV 我们正在评估SAA对中风和其他神经系统疾病的影响。另一 一系列的研究集中在血清淀粉样蛋白P成分（SAP）上，它存在于所有的淀粉样蛋白中， 提示它在淀粉样疾病的形成、发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，β-突触核蛋白，TDP-43）、tau蛋白病、CTE、ALS（SOD 1， TDP-43、C9 ORF 72）、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，并且炎症信号传导途径损害体内认知功能。我们 长期目标是确定调节SAP功能的机制，特别是在AD的情况下， 炎症性疾病。因此，该补助金的目的是描述SAP在以下方面的作用： 炎症和AD。我们已经开发和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制药公司合作设计和测试反义核酸。 寡核苷酸（ASO）作为这些病症的治疗方法。此外，我们还与 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、CSF和其他试剂验证研究 在我们的老鼠模型中。这对于我们对疾病过程的基本理解和 治疗方法的发展。

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.