Wenhui Hu, MD, PhD
Professor, Cardiovascular Sciences
Professor, Center for Metabolic Disease Research
Professor, Pathology and Laboratory Medicine
Professor, Neural Sciences
- About Me
The research interest in my lab focuses on the molecular/cellular mechanisms underlying neurogenesis and neurometabolism, which play increasingly important roles in a variety of neurodevelopmental disorders, metabolic syndrome, neurodegenerative diseases and mental illness. The challenges of discovery and translation always inspire me in medical research. I am fascinated by the creative process of identifying novel molecules and exploring novel high-impact biotechnologies. I have over 30 years of experience in molecular/cellular neuroscience, with specific training and expertise in gene regulation (NIBP, TCF4 and RGS4), signal transduction (NFkB and G protein signaling) and novel biotechnology (genome editing and gene therapy).
NIBP signaling in neurogenesis and neurometabolism:
Nuclear Factor kB (NF-kB) is a transcriptional factor that can be stimulated by many signals outside the cells through various cell signal pathways. It regulates an array of genes important in a number of biological processes (inflammation, immunity, cell survival, neural plasticity and neurogenesis) and pathological conditions (cancer, chronic inflammatory diseases and autoimmune diseases). High basal activity of NF-kB is reported in cancer cells, lymphocytes, neurons and smooth muscle cells. Sustained activation of NF-kB induced by inflammatory mediators is critical for inflammation-related cancer and other chronic diseases including NeuroAIDS. In most cases, NF-kB is held in the cytoplasm via Inhibitor of NF-kB (IkB). After phosphorylation by IkB kinase (IKK), IkB is degraded, leading to NF-kB activation. How the IKK complex is activated remains a focus of considerable research interest. Several IKK kinases have been identified, including NF-kB-inducing kinase (NIK). My research interests have been focused on the identification of novel proteins regulating IKK and its upstream kinases. One of the novel proteins, NIBP (NIK and IKK2 binding protein), has been demonstrated to increase IKK2-mediated NF-kB activation and be required for neurogenesis and neuronal polarization. NIBP is renamed as TRAPPC9 because it is a key member of transport protein particle (TRAPP) complex II, implying its importance in regulating trans-Golgi network and protein trafficking. NIBP syndrome is characterized by microencephaly, mental retardation, autism spectrum disorders, hearing loss, peculiar facial appearance, obesity and hypotonia.
Neurogenesis involves sequential differentiation of neural stem cells (NSCs) into neural progenitor cells (NPCs), various lineage-restricted blast cells, and mature neural cells. Adult neurogenesis is well established in the subgranular zone (SGZ) of hippocampus, subventricular zone (SVZ) of forebrain and the bottom of hypothalamus. The hypothalamic neurogenesis is challenged daily by the circulating nutrients and metabolic products. The hypothalamic neurons generated from NSCs as an endogenous mechanism contributes to the physiological regulation of food intake and body weight. The ongoing projects in my lab are to explore the role and mechanisms of NIBP signaling in regulating adult neurogenesis and energy homeostasis.
Inflammatory regulation of enteric neurogenesis and neuromuscular connection:
The enteric nervous system (ENS) as “the second brain in the gut” plays a critical role in regulating gut motility, secretion, absorption and mucosal homeostasis. Developmental defects in ENS contribute significantly to Hirschsprung’s disease (congenital megacolon) and other disorders of intestinal motility. Functional disorders in adult ENS are implicated in the inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS), two major diseases in the gut. In addition to genetic and environmental factors, the immune response plays a key role in the pathogenesis of IBD and IBS. Most of the immune and inflammatory responses are mediated by NF-kB signaling. Thus, NF-kB inhibition is increasingly becoming a promising target for therapy of IBD and other autoimmune diseases. However, development of this strategy has been limited due to the opposite cell type-specific actions of NF-kB signaling. In the intestinal epithelial cells, NF-kB signaling acts by maintaining the intestinal immune homeostasis and mucosal integrity, whereas NF-kB activation in immune cells (lymphocyte, macrophage, etc) and smooth muscle cells leads to the generation of various pro-inflammatory mediators that may worsen intestinal inflammation. Little is known about the role of NF-kB signaling in ENS, especially the enteric glial cell. My research aims to elucidate the importance of NIBP/NF-kB signaling in regulating enteric neurogenesis and neuroinflammation.
CRISPR/Cas9 (epi)genome editing and HIV cure:
Although the combined antiretroviral therapy (cART) has saved the life and reduced the severity of neurocognitive impairment in HIV patients, the prevalence of the milder/moderate HIV-associated neurocognitive disorders (HAND) continues to increase
. The cART can sufficiently eradicate the HIV production reservoir but does not eradicate the latent cellular and tissue reservoir including the brain and the gut. Several types of cells have been proposed as potential latent reservoir, such as resting memory T cells, microglia/macrophages and astrocytes, though these cells are known to serve primarily as productive reservoir. The quiescent NSCs may serve as a novel cellular reservoir for latent and persistent HIV infection. My research aims to identify the latent HIV reservoir in NSCs and define the molecular mechanisms underlying the reactivation and cell-selective elimination of HIV latent provirus.
Guide RNA (gRNA)-mediated CRISPR/Cas9 technology remains continuously expanded due to its rapid, easy and efficient application to manipulating endogenous genes/genomes in a wide variety of cell types and species. The CRISPR/Cas9-mediated gene/cell therapy may be a promising cure for HIV/AIDS. My research interest is focused on the “knockout” of the latent HIV provirus from host cells using Cas9 genome editing and the “shock and kill” of HIV latent cells using dCas9-mediated synergistic activator or the permanent silencing of the latent reservoir using dCas9-mediated epigenome suppressor.
Transcription factor 4 (TCF4) regulates spinogenesis and synaptogenesis:
The proneural proteins of the class I/II basic-helix-loop-helix (bHLH) family are highly conserved transcription factors. Class I bHLH proteins are expressed in a broad number of tissues during development, whereas class II bHLH protein expression is more tissue restricted. Current understanding of the function of class I/II bHLH transcription factors in both invertebrate and vertebrate neurobiology is largely focused on their function as regulators of neurogenesis. TCF4 mutations have been reliably identified in genome-wide association studies as a susceptibility risk factor for schizophrenia and have also been associated with Pitt-Hopkins syndrome, Fuchs’ endothelial corneal dystrophy, and primary sclerosing. It is unknown whether these diseases are due to defects in neurogenesis, in mature differentiated cells, or both. My research interest aims to decipher the cytoplasmic functions of Tcf4 in regulating spinogenesis and synaptogenesis of postmitotic neurons.
- Education, Training & Credentials
- Postdoctoral Fellowship, National Jewish Medical and Research Center, University of Colorado, 2000
- PhD, Peking Union Medical College and Chinese Academy of Medical Science, 1996
- MSc, The Third Military University, 1988
- MD, North Sichuan Medical College, 1982
- The Society for Neurosciences (SFN)
- The American Society of Gene and Cell Therapy (ASGCT)
- The American Gastroenterological Association (AGA)
- The American Neurogastroenterology and Motility Society (ANMS)
- The International Society for NeuroVirology (ISNV)
- The American Physiological Society (APS)