Research Projects
Neuroprotection for Ischemic Stroke
Stroke is a major cause of serious long term disability and death in the United States. Currently, there are only two primary therapeutic strategies for stroke patients; recombinant tissue plasminogen activator (tPA) and endovascular thrombectomy. Unfortunately, only ~10% of patients are able to benefit from these treatments. Developing novel neuroprotective therapies for ischemic stroke is needed. In our research, we have found that the SPAK-NKCC1 pathway is activated from ischemic injury and contributes to worsened stroke outcomes. We are examining the efficacy of the novel SPAK protein inhibitor, Zt-1a, and its ability to provide neuroprotection.
Demyelination in Traumatic Brain Injury
Traumatic brain injuries (TBI) affect more than 2.5 million people annually in the United States alone and about 75% are categorized as mild TBI (mTBI) or concussive. These patients are subjected to neurocognitive, behavioral, and psychiatric deficits. Our understanding of the pathogenesis of TBI progression and susceptibility to neurodegeneration is limited. Our research focuses on TBI-induced white matter injury, and microglia-oligodendrocyte interactions in demyelination and tissue repair. Selective deletion of Na/H exchanger 1 (NHE1) in microglial cells using transgenic conditional knockout mice (cKO) displayed improved corpus callosum integrity in MRI DTI study. We are currently investigating the underlying mechanisms.
Astrogliosis in Alzheimer’s Disease
Reactive astrocytes and astrogliosis are one of the earliest pathological markers associated with Alzheimer’s Disease (AD) development, appearing prior to amyloid-beta (Aβ) plaques, Tau neurofibrillary tangles, and cognitive deficits. However, its underlying mechanisms and possible causal relation to AD progression remain under studied. Our research has detected an upregulation of Na/H Exchanger 1 (NHE1) protein expression in reactive astrocytes in AD brains and it appears to be association with Aβ aggregates. Currently, we are investigating the impact of inhibiting the NHE1 protein in AD progression and cellular H+ homeostasis regulation.
Hippocampal Inflammation in Vascular Dementia
Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. In a murine CCH model with bilateral carotid artery stenosis (BCAS), we detected significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed increased GFAP+ astrocytes and Iba1+ microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation.
Demyelination in Ischemic Stroke Brains
Microglia regulate white matter myelination in both developing and post-injury brains and present a promising target for white matter repair. However, microglial cells are highly plastic and can acquire differential phenotypes across a range of spectrums. New single cell RNA-sequencing (scRNA-seq) studies have revealed the presence of various microglial subclusters within the brain after ischemic stroke, each displaying distinct transcriptomic profiles. Our research has found that the NHE1 protein, encoded by the Slc9a1 gene, plays a role in white matter demyelination of ischemic stroke brains. to explore the underlying mechanisms, we are conducting single cell RNA-seq transcriptiomics in conditional Slc9a1 knockout (cKO) and wild type (WT) mice.