The focus of my research is to investigate the molecular mechanisms governing Ikaros-mediated transcriptional regulation of vasoactive intestinal peptide receptor - 1 (VPACR-1) in T lymphocytes. Ikaros is a master regulator of lymphopoiesis and sets the threshold for T cell activation. Ikaros mutated mouse models develop an aggressive lymphoblastic leukemia with 100% incidence. Some human leukemias express mutated dominant negative Ikaros isoforms that inhibit full-length Ikaros DNA binding. Decreases in Ikaros binding capacity may downregulate a subset of genes capable of regulating T cell proliferation. Recently, we demonstrated that the gene for VPACR-1, a G protein coupled, anti-proliferative receptor expressed on naive T cells, is a novel gene target for Ikaros. Signaling through the anti-proliferative VPACR-1 protein may naturally impede cell cycle entry in CD4 T cells. Therefore, a decrease in Ikaros protein and/or DNA binding capacity, during certain etiologies of lymphoblastic leukemia, may
1) downregulate VPACR-1 and contribute to uncontrolled proliferation. Understanding how Ikaros regulates VPACR-1 in naive and actiavted CD4 T cells may provide insight into a crucial downstream event from Ikaros that contributes to uncontrolled proliferation in hematopoietic disorders and
2)lead to an understanding of the role Ikaros-mediated regulation of VPACR-1 plays in normal immune function, such as suppressing bystander T cell activation in certain organs including the gastrointestinal system.
Therefore, the aims of my research will be to
1) confirm bi-directional effects of Ikaros on VPACR-1 expression in primary naive and actiavted CD4 T lymphocytes
2) demonstrate which PKC pathway signaling proteins mediate TCR-dependant VPACR-1 downregulation, and
3) identify IK phosphoacceptor residues that mediate Ikaros recruitment to heterochromatin during T cell activation.
Vomhof-Dekrey EE, Sandy AR, Failing JJ, Hermann RJ, Hoselton SA, Schuh JM, Weldon AJ, Payne KJ, Dorsam GP. Radical reversal of vasoactive intestinal peptide receptors during early lymphopoiesis. Peptides. 2011, Aug 22, In press.
Dorsam GP, Benton K, Failing J, Batra S. Vasoactive intestinal peptide signaling axis in human leukemia. World J Biol Chem. 2011 Jun 26;2(6):146-60.
Vomhof-DeKrey EE, Haring JS, Dorsam GP. Vasoactive intestinal peptide receptor 1 is downregulated during expansion of antigen-specific CD8 T cells following primary and secondary Listeria monocytogenes infections. J Neuroimmunol. 2011 May;234(1-2):40-8.
Dorsam GP, Hoselton SA, Sandy AR, Samarasinghe AE, Vomhof-Dekrey EE, Dorsam ST, Schuh JM. Gene expression profiling and network analysis of peripheral blood monocytes in a chronic model of allergic asthma.
Microbiol Immunol. 2010 Sep;54(9):558-63.
Dorsam ST, Vomhof-DeKrey E, Hermann RJ, Haring JS, Van der Steen T, Wilkerson E, Boskovic G, Denvir J, Dementieva Y, Primerano D, Glenn P Dorsam. Identification of the early VIP-regulated transcriptome and its associated interactome in resting and activated murine CD4 T cells. Molecular Immunology, Volume 47, Issue 6, March 2010, Pages 1181-1194.
Benton KD, Hermann RJ, Vomhof-DeKrey EE, Haring JS, Van der Steen T, Smith J, Dovat S and GP Dorsam. A transcriptionally permissive epigenetic landscape at the vasoactive intestinal peptide receptor-1 promoter suggests a euchromatin nuclear position in murine CD4 T cells. Regulatory Peptides, Volume 158, Issues 1-3, 27 November 2009, Pages 68-76.
Vomhof-DeKrey, EE and Dorsam GP. Stimulatory and suppressive signal transduction regulates vasoactive intestinal peptide receptor-1 (VPAC-1) in primary mouse CD4 T cells. Brain Behav Immun. 2008, Oct;22(7):1024-31.
Vomhof-Dekrey, EE, Hermann RJ, Palmer MF, Benton KD, Sandy AR, Dorsam ST, Dorsam GP. TCR signaling and environment affect vasoactive intestinal peptide receptor-1 (VPAC-1) expression in primary mouse CD4 T cells./Brain Behav Immun. 2008, Oct;22(7):1032-40.
Ronni T, Payne KJ, Ho S, Bradley MN, Dorsam G, Dovat S. Human Ikaros function in activated T cells is regulated by coordinated expression of its largest isoforms. J Biol Chem. 2007 Jan 26;282(4):2538-47.
Dorsam ST, Ferrell CM, Dorsam GP, Derynck MK, Vijapurkar U, Khodabakhsh D, Pau B, Bernstein H, Haqq CM, Largman C, Lawrence HJ. The transcriptome of the leukemogenic homeoprotein HOXA9 in human hematopoietic cells. Blood. 2004 Mar 1;103(5):1676-84.
Voice JK, Dorsam G, Chan RC, Grinninger C, Kong Y, Goetzl EJ. Immunoeffector and immunoregulatory activities of vasoactive intestinal peptide. Regul Pept. 2002 Nov 15;109(1-3):199-208. Review.
Dorsam G, Goetzl EJ. Vasoactive intestinal peptide receptor-1 (VPAC-1) is a novel gene target of the hemolymphopoietic transcription factor Ikaros. J Biol Chem. 2002 Apr 19;277(16):13488-93.
Goetzl EJ, Voice JK, Shen S, Dorsam G, Kong Y, West KM, Morrison CF, Harmar AJ. Enhanced delayed-type hypersensitivity and diminished immediate-type hypersensitivity in mice lacking the inducible VPAC(2) receptor for vasoactive intestinal peptide. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13854-9.
Voice JK, Dorsam G, Lee H, Kong Y, Goetzl EJ. Allergic diathesis in transgenic mice with constitutive T cell expression of inducible vasoactive intestinal peptide receptor. FASEB J. 2001 Nov;15(13):2489-96.
Dorsam G, Voice J, Kong Y, Goetzl EJ. Vasoactive intestinal peptide mediation of development and functions of T lymphocytes. Ann N Y Acad Sci. 2000;921:79-91. Review.