The purpose of the project is to investigate the biological roles of members of the chemokine family of cytokines by studying the actions of chemokines and their receptors in vivo, particularly in mouse models of infectious and inflammatory/autoimmune disease and cancer. Correlations are made using human material when appropriate. Chemokines and their receptors are critical for leukocyte trafficking, and our experiments are directed to understanding how manipulating the chemokine system could be used to treat diseases in which leukocytes play a critical role. In addition, some chemokine receptors are expressed by cancer cells and these receptors can potentially be exploited for diagnosis and as targets for therapy. In the last year, part of the project has focused on a mouse model of skin inflammation that has features of psoriasis. The model involves injection of a cytokine, IL-23, which appears to have a role not only in psoriasis, but also in other immune-mediated diseases, such as Crohns disease. We and others had described that the chemokine receptor CCR6 is expressed by IL-23-dependent T cells that produce the cytokines IL-17 and IL-22, which are thought to be important in causing tissue injury in some autoimmune diseases. In work with colleagues, we have found that after injection of IL-23 into the skin of the mouse, a subset of gamma/delta T cells in the dermis that are able to produce IL-17 and IL-22 migrate into the epidermis as a component of the pathology of the disease, and that this migration, as well as there ability to produce the damaging cytokines, depend on the chemokine receptor CCR6 and its binding chemokine, CCL20. These data contribute important new information into the mechanism whereby CCR6 contributes to psoriasis-like pathology. In other work this year, we have also contributed to studies showing that CCR6 and CCL20 are important for the trafficking of precursors of a specialized subset of dendritic cells into the epidermis through hair follicles. A second part of the project in the last year has included using the chemokine receptor CXCR4 as a target for imaging experimental tumors in mice. Together with colleagues, we have shown that derivatives of a peptide antagonist of CXCR4 (T140), can be labeled with radioactive copper and can be used to visualize CXCR4-expressing tumors in mice by positron emission tomography (PET) scanning. CXCR4 expression in human cancers has been associated with aggressive behavior such as metastasis, and detecting a quantifying CXCR4 on tumors non-invasively may be of benefit in prognostication and in designing therapies against a given individuals cancer.

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2012
Total Cost
$1,719,066
Indirect Cost
City
State
Country
Zip Code
Singh, Satya P; Foley, John F; Zhang, Hongwei H et al. (2015) Selectivity in the Use of Gi/o Proteins Is Determined by the DRF Motif in CXCR6 and Is Cell-Type Specific. Mol Pharmacol 88:894-910
Jacobson, Orit; Yan, Xuefeng; Niu, Gang et al. (2015) PET imaging of tenascin-C with a radiolabeled single-stranded DNA aptamer. J Nucl Med 56:616-21
Singh, Satya P; Zhang, Hongwei H; Tsang, Hsinyi et al. (2015) PLZF regulates CCR6 and is critical for the acquisition and maintenance of the Th17 phenotype in human cells. J Immunol 194:4350-61
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Singh, Tej Pratap; Lee, Chang Hoon; Farber, Joshua M (2013) Chemokine receptors in psoriasis. Expert Opin Ther Targets 17:1405-22
Mabuchi, Tomotaka; Singh, Tej Pratap; Takekoshi, Tomonori et al. (2013) CCR6 is required for epidermal trafficking of γδ-T cells in an IL-23-induced model of psoriasiform dermatitis. J Invest Dermatol 133:164-71
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Nagao, Keisuke; Kobayashi, Tetsuro; Moro, Kazuyo et al. (2012) Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat Immunol 13:744-52
Jacobson, Orit; Weiss, Ido D; Szajek, Lawrence P et al. (2012) Improvement of CXCR4 tracer specificity for PET imaging. J Control Release 157:216-23
Weiss, Ido D; Jacobson, Orit; Kiesewetter, Dale O et al. (2012) Positron emission tomography imaging of tumors expressing the human chemokine receptor CXCR4 in mice with the use of ýýýýýýCu-AMD3100. Mol Imaging Biol 14:106-14

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