BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10618190
• 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/10618190
• 关键词: Acceleration; 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; Central Nervous System; 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; LoxP-flanked allele; Lysine; Macrophage; Maintenance; Malignant - descriptor; Mediating; Membrane; Microglia; Middle Cerebral Artery Infarction; Military Personnel; Mission; Modeling; Motor; Mus; NADPH Oxidase; Nature; Nervous System Physiology; Neuroglia; Neuroprotective Agents; Oligodendroglia; Oxidative Stress; Pathogenesis; Patients; Persons; 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; nervous system disorder; neuroprotection; normotensive; novel; novel therapeutic intervention; pH Homeostasis; pharmacologic; prehypertension; preservation; programs; protein expression; remyelination; scaffold; social; stroke intervention; stroke model; stroke therapy; symporter; 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，我建立了一个享誉国际的膜研究项目 离子转运蛋白及其在神经系统疾病病理生理学中的作用。我们已经推进了我们的 对离子转运蛋白(Na+-K+-Cl-共转运体、Na+/H+交换器和Na+/Ca2+)作用的认识 交换器)在疾病条件下调节中枢神经系统的离子动态平衡 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的发病率很高。 而我们的研究与改善退伍军人的医疗保健密切相关，也与退伍军人退伍军人发展基金的使命密切相关。在这段时间里 在我的RCS中，我将进行两个由BLR&D优异奖助金资助的研究项目。自从我加入VAPHS以来 研究健康科学家2012年，我与退伍军人事务部临床医生、退伍军人事务部科学家和非 退伍军人事务部科学家。目前，我在与退伍军人事务部和非退伍军人事务部科学家的六个合作项目中担任合作者。这就做 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作为治疗缺血性中风的策略的有效性 心理治疗。进化保守的WNK[“无赖氨酸”(K)]激酶及其下游的Spak/OSR1 (Ste20/SPS1相关的富含脯氨酸/丙氨酸的激酶和氧化应激反应激酶1)调节 多个离子转运体的活动，并在肾盐处理，维持动脉张力， 还有高血压。Na+-K+-2Cl-共转运蛋白亚型1(NKCC1)是WNK-1的主要底物之一。 Spak/OSR1激酶。刺激 这个 WNK-SPAK蛋白通过蛋白途径增强脑内NKCC1活性 磷酸化并通过NKCC1介导的Na+和Cl-超载导致缺血细胞损伤，细胞毒性 浮肿和兴奋性毒性。在BX002891赠款的初始资助期，我们发现WNK-Spak/OSR1 激酶参与了缺血性中风引起的脑损伤的发病机制(JCB&M.2017)。我们 结论：高血压大鼠WNK-Cab39-NKCC1信号增强与 对缺血性脑损伤的易感性，并成为抗高血压和抗缺血的新靶点 中风疗法。我们开发了一种新的WNK-SPAK抑制剂ZT-1a，它具有强大的神经保护活性 在缺血性中风动物模型中的研究(《自然通讯》2020)。从这项研究中获得的一项专利 申请(退伍军人管理局发明披露ID#2018-313)“ ZT-1a及其衍生物在脑部治疗中的应用 失调症“ 已通过美国退伍军人事务部提交。ZT-1a及其衍生物被评为新药 用于急性缺血性中风治疗的神经保护药物是创新的，将有利于退伍军人的健康。 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 脑白质损伤与组织修复的相互作用及胶质细胞导向治疗策略的探讨 TBI。小胶质细胞激活在脑白质损伤和组织修复中起着重要作用。调节PRO和PRO之间的切换 小胶质细胞/巨噬细胞的炎性和适应性表型对少突胶质细胞的分化非常重要。 重新髓鞘形成，以及突触的重塑。我们最近发现Na/H交换器亚型1蛋白 (NHE1)介导的H+外流维持小胶质细胞内pH稳态促进NADPH氧化酶 激活、自由基超氧化物的产生和细胞因子的分泌。我们报告了选择性删除 小胶质细胞Nhe1在CX3CR1-Creer中的表达；Nheflx/Flox(Nhe1 KO)小鼠保存少突胶质细胞并改进 实验性局灶性脑缺血模型感觉运动功能的恢复。Nhe1 KO小鼠展示 受控皮质中APC+成熟少突胶质细胞计数增加并保留白质完整性 冲击性脑损伤模型。特别是，创伤性脑损伤后给予NHE1蛋白抑制剂HOE642的速度加快 中风或脑外伤后小鼠神经功能的恢复。我们将进一步研究NHE1蛋白在 小胶质细胞介导的炎症在脑外伤后再髓鞘形成和组织修复中的调节。