Wenhui Hu, MD, PhD
Associate Professor, Neuroscience
Location: Room 752 MERB
Department of Neuroscience
The research interest in my lab focuses on the transcriptional regulation and signal transduction for neurogenesis, neural plasticity and neuroimmunity.
Regulation of NF-kB signaling and trans-Golgi networking: NIBP.
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. 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 growth and differentiation of neuronal cell line PC12. NIBP is renamed as TRAPPC9 because it is a key member of trafficking protein particle (TRAPP) complex II, implying its importance in regulating trans-Golgi networking. New clinical data showed that homozygous NIBP non-sense mutation is closely correlated with autosomal recessive mental retardation and neonatal microcephaly. Homozygous deletion of NIBP genome in human leads to severe developmental delay, retinal dystrophy, hearing loss and dismorphic facial features. NIBP is highly expressed in various human tumors. These clinical findings highlight the importance of NIBP in neurogenesis, mental development, neural functional integrity and tumorigenesis.
Neurogenesis involves the sequential differentiation of neural stem cells (NSCs) into neural progenitor cells (NPCs), various lineage-restricted precursor cells (RPCs), and mature neural cells. NSCs are characterized by self-renewal and multipotency. My research aims to address whether NIBP/NFkB signaling regulates cell fate decision and lineage differentiation of NSCs. The major techniques involve stem cell culture, RNA interference, cell-based functional assay, confocal imaging analysis, gene therapy, conditional gene knockout and transgenic animal modeling.
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.
Recent Medically Related Publications, Obtained from PubMed
Zhang Y, Liu J, Yao S, Li F, Xin L, Lai M, Bracchi-Richard V, Xu H, Yen W, Meng W, Liu S, Yang L, Karmally S, Liu J, Zhu H, Gordon J, Khalili K, Srinivasan S, Bethea JR, Mo X, Hu WH, NFκB Signaling Initiates Early Differentiation of Neural Stem Cells. Stem Cells :()2011 Dec 1
Sun D, Gugliotta M, Rolfe A, Reid W, McQuiston AR, Hu WH, Young H. Sustained survival and maturation of adult neural stem/progenitor cells after transplantation into the injured brain. J Neurotrauma. 2011;28(6):961-72
Li F, Hu DY, Liu S, Mahavadi S, Yen W, Murthy KS, Khalili K, Hu W, RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells. Am J Physiol Cell Physiol 299:6(C1418-29)2010 Dec
Li F, Murthy KS, Khalili K, Hu W, Cloning and characterization of rabbit Rgs4 promoter in gut smooth muscle. Gene 451:1-2(45-53)2010 Feb 1
Kuang X, Hu WH, Yan M, Wong PK. Phenylbutyric acid suppresses protein accumulation-mediated ER stress in retrovirus-infected astrocytes and delays onset of paralysis in infected mice. Neurochem Int. 2010; 57(7):738-48
Hu WH, Li F, Mahavadi S and Murthy KS. Up-regulation of RGS4 expression by interleukin-1β in colonic smooth muscle is enhanced by ERK1/2 and p38 MAPK and inhibited by PI3K/Akt/GSK3β pathway. Am J Phsyiol Cell Physiol 2009; 296(6):C1310-20
Hu WH, Li F, Mahavadi S and Murthy KS. Interleukin-1β Up-Regulates RGS4 through the Canonical IKK2/IkBa/NF-kB Pathway in Colonic Smooth Muscle. Biochem J 2008,412(1):35-43
Hu WH, Mahavadi S, Li F and Murthy KS. Upregulation of RGS4 and downregulation of CPI-17 mediate inhibition of colonic muscle contraction by IL-1b. Am J Phsyiol Cell Physiol 2007; 293(6):C1991-2000. (Full-text)
Song YD, Wilkins P, Hu WH, Murthy KS, Chen J, Lee Z, Oyesany R, Barbour SE and Fang XJ. Inhibition of calcium–independent phospholipase A2 suppresses proliferation, survival and tumorigenicity of ovarian carcinoma cells. Biochem J 2007, 406(3): 427-36. (Full-text)
Bracchi-richard V, Brambilla R, Levenson J, Hu WH, Bramwell A, Sweatt JD, Green EJ and Bethea JR. Astroglial NFκB regulates learning and memory and synaptic plasticity in female mice. J Neurochem 2008;104(3):611-23.
Zhou HP, Jarujaron S, Gurley EC, Ding H, Chen L, Studer E, Hu WH, Pandak WM, Zou T, Wang JY and Helemon PB. HIV Protease Inhibitors Increase TNF-a and IL-6 Expression in Macrophages: Involvement of the RNA-Binding Protein HuR. Atherosclerosis 2007;195(1):e134-e143. (Full-text)
Hu WH, Mahavadi S, Huang J, Li F and Murthy KS. Characterization of S1P1 and S1P2 receptor function in smooth muscle by receptor silencing and receptor protection. Am J Physiol Gastrointest Liver Physiol 2006; 291(4):G605-10 (Full-Text )
Huang J, Mahavadi S, Sriwai W, Hu WH, and Murthy KS. Gi-coupled receptors mediate phosphorylation of CPI-17 and MLC20 via preferential activation of the PI 3 kinase/ILK pathway. Biochem J 2006; 396: 193-200 (Full-Text)
Hu WH, Huang J, Mahavadi S, Li F and Murthy KS. Lentiviral siRNA silencing of sphingosine-1-phosphate receptors S1P1 and S1P2 in smooth muscle. Biochem Biophys Res Commun 2006; 343: 1038-1044 (Full-Text)
Yan D, Li F, Hall ML, Sage C, Hu WH, Giallourakis C, Upadhyay G, Ouyang XM, Du LL, Bethea JR, Chen ZY, Yaznik V and Liu XZ. An isofrom of GTPase regulator DOCK4 localizes to the stereocilia in the inner ear and binds to harmonium (USH1C). J Mol Biol 2006; 357: 755-764 (Full-Text)
Hu WH, Pendergast JS, Mo XM, Brambilla R, Bracchi-richard V, Li F, Walters WM, Blits B, He L, Schaal SM and Bethea JR. NIBP: A Novel NIK and IKKb binding protein that enhances NF-κB activation, J Biol Chem 2005; 280: 29233-29241 (Full-Text)
Brambilla R, Bracchi-richard V, Hu WH, Bramwell A, Karnally S, Green EJ and Bethea JR. Inhibition of astroglial NFκB reduces inflammation and improves functional recovery following spinal cord injury. J Exp Med 2005; 202: 145-156 (Full-Text)
Hu WH, Mo XM, Walters WM, Brambilla R, and Bethea JR. TNAP, a novel repressor of NF-kB-inducing kinase, suppresses NFkB activation. J Biol Chem. 2004; 279(34):35975-83 (Full-Text)
Hu WH, Walters WM, Xia XM, Karmally SA and Bethea JR. Neuronal glutamate transporter EAAT4 is expressed in astrocytes. Glia 2003, 44(1):12-25 (Full-Text)
Hu WH, Walters WM and Bethea JR. Identification and characterization of a novel Nogo-interacting mitochondrial protein (NIMP). J Neurochem 2002; 81(1):35-46 (Full-Text)
Hausmann ON, Hu WH, Keren-Raifman T, Witherow DS, Wang Q, Levay K, Frydel B, Z Slepak V, R Bethea JR. Spinal cord injury induces expression of RGS7 in microglia/macrophages in rats. Eur J Neurosci 2002, 15(4):602-612 (Full-Text)
Hu WH, Johnson H and Shu HB. Activation of NF-kappaB by FADD, casper, and caspase-8. J Biol Chem. 2000; 275(15):10838-44 (Full-Text)
Hu WH, Qiang WA, Liu N, Li F, Wan XST, Liu JS and Jen MF. Constitutive and inducible nitric oxide synthases after dynorphin-induced spinal cord injury. J. Chem. Neuroanatom. 2000; 17:183-197 (Full-Text)
Hu WH, Johnson H and Shu HB. Tumor necrosis factor-related apoptosis-inducing ligand receptors signal NF-kB and JNK activation and apoptosis through distinct pathways. J. Biol. Chem. 1999; 274(43):30603-30610 (Full-Text).
Shu HB, Hu WH and Johnson H. TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J. Leuko. Biol. 1999, 65(3):680-683 (Full-Text)
Hu WH, Li F, Qiang WA, Liu N, Wang GQ, Xiao J, Liu JS, Liao WH, Jen MF. Dual role for nitric oxide in dynorphin spinal neurotoxicity. J. Neurotrauma 1999, 16(1):85-98