Type 1 diabetes (T1D) is an inflammatory disease of the pancreatic islets that afflicts millions of people worldwide. Although the etiological factors that trigger the disease vary, the common pathological outcome of T1D is the destruction of insulin-producing p cells by inflammatory cells through a process called insulitis. Development of insulitis requires coordinated expression of a large number of genes that mediate the activation, migration and effector functions of inflammatory cells. These include genes that encode cytokines, chemokines, and cytotoxic enzymes. While it is well recognized that expression of these genes is tightly regulated at the transcriptional level, the nature of the transcription factors involved and the mechanisms of their action in T1D are not well understood. Recent studies from several laboratories including ours indicate that the nuclear factor (NF)-KB family of transcription factors plays crucial roles in T1D. Thus, in both mice and humans, T1D is associated with heightened NF-icB activation, whereas NF-KB deficiency in mice renders them resistant to the disease. Importantly, inhibiting NF-KB activities is highly effective in suppressing models of T1D. Therefore, NF-icB has emerged as a long sought-after transcriptional regulator of T1D. However, NF-icB is expressed not only by lymphoid and myeloid cells that cause insulitis, but also by cells of the non-immune systems including p cells of the pancreatic islets that are destroyed by insulitis. NF-KB-based therapeutic strategies would be most effective if they selectively target those cells or NF-xB pathways that are directly responsible for the pathogenesis of T1D. We hypothesize that NF-KB expressed by different cell types activates different sets of genes and plays different roles in T1D: NF-KB expressed by inflammatory cells orchestrates their activation and effector function by activating pro- inflammatory genes whereas NF-KB expressed by pancreatic /3cells regulates their death and survival by activating apoptotic genes.
The specific aims of this proposal are: 1) To test the hypothesis that NF-KB expressed by lymphoid and myeloid cells promotes type 1 diabetes by activating pro-inflammatory genes. 2) To test the hypothesis that NF-KB expressed by pancreatic (3cells dictates their fate in type 1 diabetes by activating apoptotic genes. 3) To test the hypothesis that the NF-KB-IL-23 axis plays a key role in the pathogenesis of type 1 diabetes. 4) To treat type 1 diabetes by blocking inducible NF-KB activity. Information generated from the proposed studies will help establish which cell(s) and which NF-KB pathway(s) should be selectively targeted for the treatment of T1D. A new class of NF-KB inhibiting drugs may then be developed to treat T1D.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK070691-04
Application #
7745453
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2007-01-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$297,973
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Ruan, Qingguo; Kameswaran, Vasumathi; Zhang, Yan et al. (2011) The Th17 immune response is controlled by the Rel-RORýý-RORýý T transcriptional axis. J Exp Med 208:2321-33
Li, Li; Ruan, Qingguo; Hilliard, Brendan et al. (2011) Transcriptional regulation of the Th17 immune response by IKK(alpha). J Exp Med 208:787-96
Ruan, Qingguo; Wang, Ting; Kameswaran, Vasumathi et al. (2011) The microRNA-21-PDCD4 axis prevents type 1 diabetes by blocking pancreatic beta cell death. Proc Natl Acad Sci U S A 108:12030-5
Ruan, Qingguo; Zheng, Shi-Jun; Palmer, Scott et al. (2010) Roles of Bcl-3 in the pathogenesis of murine type 1 diabetes. Diabetes 59:2549-57
Ludwinski, Maciej W; Sun, Jing; Hilliard, Brendan et al. (2009) Critical roles of Bim in T cell activation and T cell-mediated autoimmune inflammation in mice. J Clin Invest 119:1706-13
Ruan, Qingguo; Kameswaran, Vasumathi; Tone, Yukiko et al. (2009) Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 31:932-40
Sun, Honghong; Gong, Shunyou; Carmody, Ruaidhri J et al. (2008) TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell 133:415-26
Carmody, Ruaidhri J; Ruan, Qingguo; Palmer, Scott et al. (2007) Negative regulation of toll-like receptor signaling by NF-kappaB p50 ubiquitination blockade. Science 317:675-8