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Assistant Professor, Neuroscience Location: Room 752 MERB Telephone: 215-707-5164 Fax: 215-707-4888 Email: whu@temple.edu
Department of Neuroscience
The research in my lab is directed to the gene regulation and signal transduction. Specifically, I am interested in identifying and characterizing novel regulators for the signaling pathways of transcription factor NF-κB, which plays a critical role in neural plasticity, cancer, inflammation and immunity. Several novel proteins have been identified. My current research supported by NIH-R01 is focused on the transcriptional and posttranscriptional regulation of key signaling components mediating smooth muscle contraction/relaxation.
Regulation of NF-kB signaling pathways: NIBP.
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-κB activation and be required for growth and differentiation of neuronal cell line PC12. However, it is not known whether NIBP is essential for neuronal differentiation and survival in primary neurons or neural stem cells from central, peripheral and enteric nervous system. In addition, much more functions of NIBP and their mechanisms remain to be elucidated. Due to high expression of NIBP in neuron and cancer cells, we hypothesize that NIBP may play an important role in the neurogenesis and tumorigenesis. To test this, the state-of-the-art genetic, molecular and biochemical approaches as well as powerful confocal imaging and multiple-labeling immunofluorescent staining are utilized. Specifically, lentivirus-mediated inducible siRNA system is used both in vitro and in vivo. Generation of floxed NIBP transgenic mice will widen several novel fields to study the in vivo function and mechanisms of NIBP.
Cytokine-induced regulation of signaling targets for smooth muscle contraction
Parallel comparative studies are performed using primary cell and organ cultures as well as animal colitis models. Smooth muscle cells are the major components of hollow organs and capable of synthesizing a variety of pro- and anti-inflammatory mediators, including cytokines, chemokines, growth factors, and cell-adhesion molecules. Distinct patterns of inflammatory mediators that either decrease (Th2 model) or increase (Th1 model) the contractility of smooth muscle cells have been demonstrated. The specific signaling targets mediating contraction that are affected by these inflammatory mediators have not been identified. We hypothesize that the major pro-inflammatory cytokine IL-1β, acting via transcriptional (especially NF-κB) and post-transcriptional (focusing on mRNA stability) mechanisms, inhibits smooth muscle contractility by inducing or suppressing the expression of critical signaling targets mediating contraction. Initial contraction of intestinal smooth muscle involves sequential activation of G proteins and PLC-β, resulting in IP3-dependent Ca2+ release and myosin light chain (MLC) kinase-stimulated phosphorylation of MLC20. Sustained Ca2+-independent contraction is mediated by Rho kinase-stimulated phosphorylation of the regulatory subunit of MLC phosphatase (MYPT1) and/or PKC-stimulated phosphorylation of CPI-17, an endogenous inhibitor of MLC phosphatase. We have identified four major targets, RGS proteins (RGS4 and RGS12), SERCA2 and CPI-17 and two regulatory enymes NOX1 and NOX4 in the signaling cascades that mediate IL-1β-induced inhibition of the initial and sustained contraction. Most of these targets are regulated through NF-κB pathways. These studies will provide a comprehensive analysis of the effects of a prototypic inflammatory cytokine on the major signaling targets mediating smooth muscle contraction.
RGS4 is a major member of R4 family RGS proteins and modulates the duration and quality of Gaq-mediated signaling. RGS4 plays an important role in neuropsychiatric disorders and cardiovascular diseases. We demonstrated for the first time that IL-1β up-regulates RGS4 expression at both mRNA and protein level in gut smooth muscle cells. Current research is focused on exploring the molecular mechanisms and signaling pathways for IL-1β-induced up-regulation of RGS4 expression.
Recent Medically Related Publications, Obtained from PubMed
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, Feb 8; [Epub ahead of print]
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
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Wenhui Hu, MD, PhD 
Nuclear Factor κB (NF-
κB) 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 and neural plasticity) and pathological conditions (cancer, chronic inflammatory diseases and autoimmune diseases). High basal activity of NF-κB is reported in cancer cells, lymphocytes, neurons and smooth muscle cells. Sustained activation of NF-κB induced by inflammatory mediators is critical for inflammation-related cancer and other chronic diseases. However, the origins and mechanisms of NF-κB activation (constitutive or inducible) are not well understood. In most cases, NF-κB is held in the cytoplasm via Inhibitor of NF-kB (IkB). After phosphorylation by IκB kinase (IKK), IκB is degraded, leading to NF-κB activation. How the IKK complex is activated remains a focus of considerable research interest. Several IKK kinases have been identified, including NF-
κB-inducing kinase (NIK).