Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that afflicts approximately 400,000 people in the United States alone. Currently there is no cure for MS and only seven """"""""disease-modifying drugs"""""""" have been approved by the FDA to treat relapsing, but not primary progressive, forms of MS. Although the genetic and environmental factors that trigger the disease vary, the common pathological outcome of MS is the destruction of oligodendrocytes and their associated neuronal axons through a process called encephalomyelitis. Development of encephalomyelitis requires coordinated expression of a unique class of genes called inflammatory genes. These genes encode inflammatory proteins that mediate the activation, migration, and effector function of inflammatory cells that cause encephalomyelitis. Inhibiting the functions of this class of genes may be effective for ameliorating MS. However, because MS is mediated by many, if not all, inflammatory genes, inhibiting one or a few of them may have limited efficacies. This competitive renewal application is inspired by our recent discovery that the transcription factor c Rel, a lymphoid and myeloid member of the Rel/nuclear factor-?B (NF-?B) family, controls (i) the expression of multiple inflammatory genes, and (ii) the development of the inflammatory Th17 cells. The goal of this application is to elucidate the mechanisms through which c-Rel controls the Th17 response, and to develop c-Rel-blocking drugs for the treatment of inflammatory diseases. The hypotheses to be tested are: (i) c-Rel is a primary transcription factor of the Th17 response, and (ii) c-Rel is a prime drug target for treating multiple sclerosis.

Public Health Relevance

Information generated from these studies will not only advance our understanding of the Th17 and c-Rel biology, but also aid in developing novel c-Rel blocking drugs for the treatment of inflammatory diseases. Therefore, this project may advance both scientific knowledge and clinical practice.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Fayngerts, Svetlana A; Wang, Zhaojun; Zamani, Ali et al. (2017) Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2. Nat Immunol 18:1353-1360
Gong, Shunyou; Osei, Ebenezer S; Kaplan, David et al. (2015) CD317 is over-expressed in B-cell chronic lymphocytic leukemia, but not B-cell acute lymphoblastic leukemia. Int J Clin Exp Pathol 8:1613-21
Porturas, Thomas P; Sun, Honghong; Buchlis, George et al. (2015) Crucial roles of TNFAIP8 protein in regulating apoptosis and Listeria infection. J Immunol 194:5743-50
Sun, Honghong; Lou, Yunwei; Porturas, Thomas et al. (2015) Exacerbated experimental colitis in TNFAIP8-deficient mice. J Immunol 194:5736-42
Lou, Yunwei; Sun, Honghong; Morrissey, Samantha et al. (2014) Critical roles of TIPE2 protein in murine experimental colitis. J Immunol 193:1064-70
Fayngerts, Svetlana A; Wu, Jianping; Oxley, Camilla L et al. (2014) TIPE3 is the transfer protein of lipid second messengers that promote cancer. Cancer Cell 26:465-78
Yan, Qin; Carmody, Ruaidhri J; Qu, Zhonghua et al. (2012) Nuclear factor-?B binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome. Proc Natl Acad Sci U S A 109:14140-5
Johnson, Derek S; Chen, Youhai H (2012) Ras family of small GTPases in immunity and inflammation. Curr Opin Pharmacol 12:458-63
Gus-Brautbar, Yael; Johnson, Derek; Zhang, Li et al. (2012) The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras. Mol Cell 45:610-8
Wang, Zhaojun; Fayngerts, Svetlana; Wang, Peng et al. (2012) TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection. Proc Natl Acad Sci U S A 109:15413-8

Showing the most recent 10 out of 18 publications