BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10373039
• 负责人: Dandan Sun
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373039
• 关键词: Achievement; Acute; Adult; Affect; Alanine; Alteplase; Animal Model; Antihypertensive Agents; Attenuated; Autopsy; Award; Behavioral; Brain; Brain Diseases; Brain Injuries; Cardiovascular Diseases; Carrier Proteins; Cause of Death; Cerebral Edema; Cerebrospinal Fluid; Cerebrovascular Disorders; Cognitive; Collaborations; Communication; Development; Disclosure; Disease; Edema; Exhibits; Free Radicals; Functional disorder; Funding; Grant; Health; Healthcare; Hemorrhage; High Prevalence; Homeostasis; Human; Hybrids; Hydrocephalus; Hypertension; Impairment; Inbred SHR Rats; Inbred WKY Rats; Inflammation; Inflammatory; International; Ion Transport; Ions; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Kidney; Knockout Mice; Legal patent; Lysine; Maintenance; Malignant - descriptor; Mediating; Membrane; Microglia; Middle Cerebral Artery Infarction; Military Personnel; Mission; Modeling; Motor; Mus; NADPH Oxidase; Nature; Nervous System Physiology; Neuraxis; Neuroglia; Neuroprotective Agents; Oligodendroglia; Oxidative Stress; Pathogenesis; Patients; Persons; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Play; Post-Traumatic Stress Disorders; Predisposition; Production; Proline; Protein Isoforms; Proteins; Rattus; Recovery of Function; Regulation; Reporting; Research; Research Project Grants; Rights; Role; Scientist; Sensorimotor functions; Signal Transduction; Sodium Chloride; Stroke; Structure of choroid plexus; Superoxides; Synapses; Technology Transfer; Therapeutic; Translational Research; Traumatic Brain Injury; United States Department of Veterans Affairs; Veterans; brain tissue; burden of illness; career; cell injury; chloride-cotransporter potassium; comorbidity; controlled cortical impact; cytokine; cytotoxic; disability; excitotoxicity; health care service; hypertensive; improved; improved outcome; inclusion criteria; inhibitor; injury and repair; innovation; invention; macrophage; nervous system disorder; normotensive; novel; novel therapeutic intervention; pH Homeostasis; prehypertension; preservation; programs; protein expression; remyelination; scaffold; social; stroke intervention; stroke model; stroke therapy; therapeutic target; tissue repair; translational approach; white matter; white matter injury

PROJECT ABSTRACT Over the past 25 years, I have established an internationally renowned research program on studying membrane ion transport proteins and their functions in pathophysiology of neurological diseases. We have advanced our understanding about roles of ion transport proteins (Na+-K+-Cl- cotransporter, Na+/H+ exchanger and Na+/Ca2+ exchangers) in regulation of ionic homeostasis in the central nervous system under disease conditions such as acute ischemic stroke and traumatic brain injury (TBI). These brain disorders have high prevalence in veterans and our research is closely related to improving veterans’ health care, and the mission of VA BLRD. In the period of my RCS, I will conduct two research projects funded by BLR&D merit grants. Since I joined VAPHS as a Research Health Scientist in 2012, I have built broad collaborations with VA clinicians, VA scientists, and non- VA scientists. I currently serve as a Co-I on six collaborative projects with VA and non-VA scientists. I will continue to contribute my expertise to these collaborations. In the I01BX002891 study, we will investigate efficacy of SPAK inhibitor ZT-1a as a strategy for ischemic stroke therapy. Evolutionary conserved WNK ["with no lysine" (K)] kinases and the downstream SPAK/OSR1 (Ste20/SPS1-related proline/alanine-rich kinase and oxidative stress-responsive kinase 1) kinases regulate activities of multiple ion transporters and play important roles in renal salt handling, maintenance of arterial tone, and hypertension. Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) is one of the major substrates of the WNK- SPAK/OSR1 kinases. Stimulation of the WNK-SPAK kinases increased brain NKCC1 activity via protein phosphorylation and led to ischemic cell damage through NKCC1-mediated Na+ and Cl- overload, cytotoxic edema and excitotoxicity. In the initial funding period of BX002891 grant, we discovered that WNK-SPAK/OSR1 kinases are involved in the pathogenesis of ischemic stroke-induced brain damages (JCB&M. 2017). We concluded that augmented WNK-Cab39-NKCC1 signaling in hypertensive rats is associated with an increased susceptibility to ischemic brain damage and presents as a novel target for anti-hypertensive and anti-ischemic stroke therapy. We developed a novel WNK-SPAK inhibitor ZT-1a which shows robust neuroprotective activity in animal models of ischemic stroke (Nature Communications 2020). Derived from this research, a patent application (VA Invention Disclosure ID# 2018-313) “ Therapeutic application of ZT-1a and derivatives for brain disorders” has been filed via U.S. Department of Veterans Affairs. Assessing ZT-1a and its derivatives as novel neuroprotective drugs for acute ischemic stroke therapies is innovative and will benefit veterans’ health. In the second study funded by I01BX004625, we will investigate the roles of microglia-oligodendrocyte interactions in white matter injury and tissue repair and to explore glia-oriented therapeutic strategies for treating TBI. Microglia activation plays a role in white matter injury and tissue repair. Regulation of a switch between pro- inflammatory and adaptive phenotypes of microglia/macrophage is important for oligodendrocyte differentiation, remyelination, as well as remodeling of synapses. We recently discovered that Na/H exchanger isoform 1 protein (NHE1)-mediated H+ efflux maintains microglial intracellular pH homeostasis to promote NADPH oxidase activation, free radical superoxide production, and cytokine secretion. We reported that selective deletion of microglial Nhe1 in the Cx3cr1-CreER;Nheflox/flox (Nhe1 KO) mice preserved oligodendrocytes and improved sensorimotor function recovery in an experimental focal ischemic stroke model. Nhe1 KO mice exhibited increased APC+ mature oligodendrocyte counts and preserved white matter integrity in a controlled cortical impact-induced TBI model. Especially, post-TBI administration of the NHE1 protein inhibitor HOE642 accelerated neurological function recovery in mice after either stroke or TBI. We will further investigate NHE1 protein in modulating microglia-mediated inflammation in remyelination and tissue repair after TBI.

项目摘要 在过去的25年里，我建立了一个国际知名的膜研究项目 离子转运蛋白及其在神经系统疾病病理生理学中的功能。我们已经先进了我们的 了解离子转运蛋白（Na+-K+-Cl- 协同转运蛋白、Na+/H+ 交换器和 Na+/Ca2+）的作用 交换器）在疾病条件下调节中枢神经系统的离子稳态 急性缺血性中风和创伤性脑损伤（TBI）。这些脑部疾病在退伍军人中发病率很高 我们的研究与改善退伍军人的医疗保健以及 VA BLRD 的使命密切相关。期间 在我的 RCS 中，我将开展两个由 BLR&D 奖学金资助的研究项目。自从我加入 VAPHS 以来 自 2012 年担任研究健康科学家以来，我与 VA 临床医生、VA 科学家和非 弗吉尼亚州科学家。我目前担任 VA 和非 VA 科学家的六个合作项目的 Co-I。我会 继续为这些合作贡献我的专业知识。 在 I01BX002891 研究中，我们将研究 SPAK 抑制剂 ZT-1a 作为缺血性中风策略的功效 治疗。进化保守的 WNK [“不含赖氨酸”(K)] 激酶和下游 SPAK/OSR1 （Ste20/SPS1 相关脯氨酸/丙氨酸富集激酶和氧化应激反应激酶 1）激酶调节 多种离子转运蛋白的活性，并在肾盐处理、维持动脉张力、 和高血压。 Na+-K+-2Cl- 协同转运蛋白亚型 1 (NKCC1) 是 WNK- 的主要底物之一 SPAK/OSR1 激酶。刺激 这 WNK-SPAK 激酶通过蛋白质增加大脑 NKCC1 活性 磷酸化并通过 NKCC1 介导的 Na+ 和 Cl- 超载、细胞毒性导致缺血性细胞损伤 水肿和兴奋性毒性。在 BX002891 资助的初始资助期间，我们发现 WNK-SPAK/OSR1 激酶参与缺血性中风引起的脑损伤的发病机制（JCB&M.2017）。我们 得出的结论是，高血压大鼠中 WNK-Cab39-NKCC1 信号传导的增强与 对缺血性脑损伤的易感性，可作为抗高血压和抗缺血的新靶点 中风治疗。我们开发了一种新型 WNK-SPAK 抑制剂 ZT-1a，它具有强大的神经保护活性 在缺血性中风的动物模型中（Nature Communications 2020）。根据这项研究，获得了一项专利 申请（VA 发明披露 ID# 2018-313）“ ZT-1a及其衍生物对脑的治疗应用 紊乱” 已通过美国退伍军人事务部提交。评估 ZT-1a 及其衍生物的新颖性 用于急性缺血性中风治疗的神经保护药物具有创新性，将有益于退伍军人的健康。 在 I01BX004625 资助的第二项研究中，我们将研究小胶质细胞-少突胶质细胞的作用 白质损伤和组织修复之间的相互作用，并探索以神经胶质细胞为导向的治疗策略 创伤性脑损伤。小胶质细胞激活在白质损伤和组织修复中发挥作用。亲之间的切换调节 小胶质细胞/巨噬细胞的炎症和适应性表型对于少突胶质细胞分化很重要， 髓鞘再生以及突触重塑。我们最近发现 Na/H 交换异构体 1 蛋白 (NHE1) 介导的 H+ 外流维持小胶质细胞胞内 pH 稳态以促进 NADPH 氧化酶 激活、自由基超氧化物产生和细胞因子分泌。我们报告了选择性删除 Cx3cr1-CreER;Nheflox/flox (Nhe1 KO) 小鼠中的小胶质细胞 Nhe1 保留了少突胶质细胞并改善了 实验性局灶性缺血性中风模型中感觉运动功能的恢复。 Nhe1 KO 小鼠表现出 增加 APC+ 成熟少突胶质细胞计数并保留受控皮质中白质的完整性 冲击诱发的 TBI 模型。特别是，TBI 后施用 NHE1 蛋白抑制剂 HOE642 加速了 中风或创伤性脑损伤后小鼠的神经功能恢复。我们将进一步研究 NHE1 蛋白 调节 TBI 后髓鞘再生和组织修复中小胶质细胞介导的炎症。