BLRD Research Career Scientist Award Application

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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.