Inflammatory bowel diseases (IBD) are chronic, relapsing and tissue destructive diseases. T helper type l (Thl) cells secreting TNF-alpha and IFN-gamma have been emphasized in ulcerative colitis, while Th2 cells may be more closely associated with Crohn's disease. However, either Thl or Th2 cells can induce colitis in several mouse models; hence the precise causes of these two forms of IBD are incompletely understood. It has recently been shown that the mechanisms of IBD involve antigen- dependent interactions between CD4+ T cells and antigen-presenting cells (APCs) as well as genetic factors. A major deficiency in understanding the steps responsible for IBD, is the lack of comprehension for the role innate and early acting factors play in mucosal immune responses. Chemokines are a family of proteins that are resistant to inactivation by pH or proteolysis as well as affect the chemotaxis and angiogenesis of leukocytes and endothelial cells. Therefore, chemokines no doubt play a pivotal role in the regulation (i.e., initiation, maintenance, and suppression) of mucosal inflammation and tissue destruction. In fact, human interleukin-8 (IL-8), IFN-gamma inducible protein - l0 (IP-l0), CXCR3 (the receptor for IP-10), RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted), and MCP-l/JE (monocyte chemotactic protein-1) have been shown to be unregulated at the sites of mucosal inflammation (IBD). The current proposal stems from our recent findings that RANTES, IP-10, IL- 8, lymphotactin (Lptn), but not MCP-l/JE, can enhance mucosal adaptive immune responses. Since these chemolcines act at several levels, four Specific Aims will be addressed to elucidate the precise role of these chemokines and their corresponding receptors in IBD.
The first aim will define the regulatory role of chemokines that are secreted by CD45RBHI CD4+ T cells subsets, which cause experimental IBD after adoptive transfer.
The second aim will assess the role of mIL-8Rh (murine IL- 8/GCP2 receptor), CCR5 (a RANTES receptor), CXCR3, and XCRl (Lptn receptor) interactions in the CD45RBHI CD4+ T cell transfer model of murine IBD.
The third aim will evaluate the chemokines, cytokines, and corresponding receptors that are expressed by the IBD inducers (CD45RBHI) and IBD suppressors (CDRB45LO) CD4+ T cells subsets.
The fourth aim will ascertain the angiogenic or angiostatic factors and cell signaling molecules that are expressed or activated, respectively, by chemokines that regulate IBD. These proposed studies will provide important and novel information regarding the cellular and molecular mechanisms that chemokines use to induce, maintain, and suppress mucosal inflammation and angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK058967-01
Application #
6288595
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2000-09-30
Project End
2003-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$70,785
Indirect Cost
Name
Morehouse School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30310
Johnson-Holiday, Crystal; Singh, Rajesh; Johnson, Erica et al. (2011) CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9-dependent fashion. Int J Oncol 38:1279-85
Johnson-Holiday, Crystal; Singh, Rajesh; Johnson, Erica L et al. (2011) CCR9-CCL25 interactions promote cisplatin resistance in breast cancer cell through Akt activation in a PI3K-dependent and FAK-independent fashion. World J Surg Oncol 9:46
Johnson, Erica L; Singh, Rajesh; Singh, Shailesh et al. (2010) CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion. World J Surg Oncol 8:62
Singh, Shailesh; Singh, Rajesh; Singh, Udai P et al. (2009) Clinical and biological significance of CXCR5 expressed by prostate cancer specimens and cell lines. Int J Cancer 125:2288-95
Singh, Shailesh; Singh, Rajesh; Sharma, Praveen K et al. (2009) Serum CXCL13 positively correlates with prostatic disease, prostate-specific antigen and mediates prostate cancer cell invasion, integrin clustering and cell adhesion. Cancer Lett 283:29-35
Singh, Rajesh; Lillard Jr, James W (2009) Nanoparticle-based targeted drug delivery. Exp Mol Pathol 86:215-23
Singh, Udai P; Singh, Rajesh; Singh, Shailesh et al. (2008) CXCL10+ T cells and NK cells assist in the recruitment and activation of CXCR3+ and CXCL11+ leukocytes during Mycobacteria-enhanced colitis. BMC Immunol 9:25
Singh, Rajesh; Singh, Shailesh; Lillard Jr, James W (2008) Past, present, and future technologies for oral delivery of therapeutic proteins. J Pharm Sci 97:2497-523
Singh, Udai P; Singh, Shailesh; Ravichandran, Palaniappan et al. (2004) Viral macrophage-inflammatory protein-II: a viral chemokine that differentially affects adaptive mucosal immunity compared with its mammalian counterparts. J Immunol 173:5509-16
Singh, Udai P; Singh, Shailesh; Taub, Dennis D et al. (2003) Inhibition of IFN-gamma-inducible protein-10 abrogates colitis in IL-10-/- mice. J Immunol 171:1401-6

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