Education:
University of Birmingham, England
1976 B. Sc. (Hons) Biochemistry
1979 Ph.D. Immunology

1. Summary of Research Interests.
TNF-receptor family members play a key role in inflammation, innate and adaptive immunity and apoptosis. The goals of our lab are two fold. First, we are addressing fundamental questions about how the prototypic receptor, TNF-R1, initiates different responses. Second, we are investigating how TNF-R1 and other family members regulate apoptosis in pulmonary myofibroblasts. These latter studies are aimed at furthering our understanding of the mechanisms that lead to the development of pulmonary fibrosis.

2. The subcellular localization of the TNF receptor, TNF-R1, determines signaling responses.

A central question in TNF-R1 signaling is how a single receptor is capable of initiating many different responses using a limited repertoire of signaling molecules. In recent and current studies, we are addressing the possibility that signal diversity is regulated, at least in part, by the subcellular localization of the receptor. It in now well established that TNF-R1 exists in several subcellular compartments. Low levels of the receptor are expressed on the cell surface, both in the plasma membrane and in lipid rafts. In addition, the receptor is found in the trans-Golgi network. We have also shown that the localization of the receptor and its signaling responses are controlled by kinases that phosphorylate the membrane proximal region of the cytoplasmic domain. We and others have recently shown that internalization of TNF-R1 is required for the activation of some signaling responses, but is dispensible for others. Using siRNA approaches, we have knocked down components of the internalization machinery to address the role and level of internalization in TNF-R1 signaling.

3. TRUSS, a TNF receptor scaffolding protein.
Since internalization of TNF-R1 is important in the initiation of some TNFα-induced signaling responses we thought it likely that signaling and/or internalization would be regulated by interactions between the cytoplasmic domain of the receptor and other signaling proteins. To address this question, we cloned a novel protein called TRUSS that interacts with the membrane proximal region of TNF-R1. We are particularly interested in the functions of TRUSS in TNF-R1 signaling. Recent studies have suggested that TRUSS plays an important role in NF-κB and JNK activation. In addition, TRUSS contains several putative dileucine and tyrosine-based internalization motifs in its C-terminal region and we are currently investigating the possibility that this region of TRUSS may play a role in TNF-R1 internalization, a finding that is consistent with the observation that TRUSS is localized to vesicles, when over-expressed. Hypotheses that we are currently addressing are shown in Figure 1. In collaboration with Dr. Raul Torres' lab, we are creating a conditional knockout mouse to allow us to further explore the role of TRUSS in TNF-α signaling in inflammation and adaptive immunity in vivo. In addition, we are collaborating with Dr. Gongyi Zhang's lab to determine the 3-dimensional structure of TRUSS.

4. Mechanism of myofibroblast apoptosis and survival in pulmonary fibrosis.
Usual interstitial pneumonitis (UIP) is a fibrotic disease of the alveolar spaces and pulmonary interstitium. The mean survival of patients diagnosed with this disease is less than three years. Impaired gas exchange results from a gradual stiffening of the lung parenchyma as excessive amounts of collagen matrix is synthesized by fibroblasts and myofibroblasts which accumulate in large numbers in the lungs of patients with UIP. During normal wound repair, myofibroblasts usually undergo apoptosis and disappear at the completion of wound repair. However, in the lungs of patients with UIP, these cells persist and accumulate. The mechanisms controlling myofibroblast apoptosis and survival are poorly understood. We are currently addressing three inter-related questions about the mechanism of myofibroblast survival in UIP. First, since these cells do not undergo apoptosis, we are investigating the role of lung expression of the survival factor, IGF-I, in protecting myofibroblasts from physiologic apoptosis. Second, we are investigating the fundamental mechanisms by which myofibroblasts undergo physiologic apoptosis, and third, we are addressing how this is dysregulated in UIP. In addition to basic questions, this aspect of our work offers the possibility of translational research projects.

Selected Bibliography

• V. Cottin, A. Van Linden and D.W.H. Riches 1999. Phosphorylation of TNF Receptor CD120a (p55) by p42mapk/erk2 Induces Changes in its Subcellular Localization. J. Biol. Chem.274:32975-32987.
• S-t Uh, A. Van Linden and D.W.H. Riches. 2000. Phosphorylation of 130 and 95 kDa substrates associated with tumor necrosis factor-a receptor CD120a (p55). J. Biol. Chem. 275:793-800.
• A.A. Van Linden, V. Cottin, C. Leu and D.W.H. Riches. 2000. Phosphorylation of the membrane proximal region of TNF receptor CD120a (p55) at ERK consensus sites. J. Biol. Chem. 275:6996-7003.
• E.D. Chan andD.W.H. Riches. 2001. IFNγ and LPS induction of iNOS is modulated by ERK, JNK/SAPK and p38mapk in a mouse macrophage cell line. Am. J. Physiol. Cell Physiol. 280:C441-C450.
• V. Cottin A.A. Van Linden and D.W.H. Riches. 2001. Phosphorylation of TNF receptor CD120a (p55) recruits Bcl-2 and protects against apoptosis. J. Biol. Chem. 276:17252-17260
• E.D. Chan, K.R. Morris, J.T. Belisle, P. Hill, L.K. Remigio, P.J. Brennan and D.W.H. Riches. 2001 Induction of iNOS-NO by lipoarabinomannan of Mycobacterium tuberculosis is mediated by MEK1-ERK, MKK7-JNK and NF-κB signaling pathways. Infect. Immunity. 69:2001-2010.
• V. Cottin, J.E.S. Doan and D.W.H. Riches. 2002. Restricted localization of the TNF receptor CD120a to lipid rafts. A novel role for the death domain. J. Immunol. 168:4095-4102.
• G.W. Kerby, V. Cottin, F.W. Hoffmann, F.J. Accurso, E.D. Chan, V.A. Fadok and D.W.H. Riches. 2002. Differential regulation of MAP kinase activity and apoptosis in macrophages in response to TNF-α and hyperosmolarity. Implications for early pulmonary inflammation in cystic fibrosis. Am. J Physiol. (Lung Cell. Molec. Physiol.) 283:L188-L197.
• M.W. Wynes and D.W.H. Riches. 2003. Induction of macrophage insulin-like growth factor-I expression by the Th2 cytokines IL-4 and IL-13. J. Immunol. 171:3550-3559
• S.M. Soond, J.L. Terry, J.D. Colbert and D.W.H. Riches. 2003. TRUSS, a novel tumor necrosis factor receptor-1 scaffolding protein that regulates the activation of transcription factor NF-κB. Mol. Cell. Biol. 23:8334-8443
• D.W.H. Riches. 2004. PPARγ - A legitimate target to control pulmonary inflammation? Am. J. Respir. Crit. Care Med. 169:145-146.
• A.A. Van Linden, V. Cottin, S.K. Frankel and D.W.H. Riches. 2005. Hierarchical phosphorylation of the TNF- receptor, TNF-R1, by p42mapk/erk2 at basic Pro-directed kinase sites. Biochemistry. 44:6980-6989.
  
  M.W. Wynes and D.W.H. Riches 2005. Transcription of macrophages IGF-I exon 1 is positively regulated by the 5’-untranslated region an negatively regulated by the 5’-flanking region. Am. J. Physiol. Lung Cell. Mol. Physiol. 288:L1089-L1098.
• S.K. Frankel, G.P. Cosgrove, M.W. Wynes, S-I Cha, C. Cool, B.L. Edelman, K.K Brown and D.W.H. Riches. 2006. TNF- sensitizes normal and fibrotic human lung fibroblasts to Fas-induced apoptosis. Amer. J. Respir. Cell Molec. Biol. 34:293-304.
• A.G. Kostyk, K.M. Dahl, M.W. Wynes, L.A. Whittaker, D.J. Weiss, R. Loi and D.W.H. Riches. 2006 Regulation of chemokine production by NaCl occurs independently of cystic fibrosis transmembrane conductance regulator in macrophages. Am. J. Pathol. 169:12-20.

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