T lymphocytes are important regulators of mammalian immune response to pathogens and tumor cells, and are important effectors in allergenic reactions, transplant rejection and autoimmunity. Transcription factors regulate T cells differentiation from progenitors to mature cells, as well as quiescence, activation and programmed cell death. Therefore, alteration in transcription factor function may result in dysfunction of immune system responses and disease. A program of supervised training in immunology is proposed to elucidate the role that CTIP2, a novel transcriptional modulator, plays in T cells and to characterize the molecular basis of the transcriptional mechanisms underlying this function. The long term objectives of this proposal are to understand how nuclear transcriptional modulators regulate gene expression in T lymphocytes and determine their role in differentiation, quiescence and activation. To this end, they recently isolated a novel family of C2H2 zinc finger proteins, CTIP1 and CTIP2, highly and differentially expressed in the immune system. Transcriptional repression mediated by CTIPs is independent of trichostatin A sensitive histone deacetylation. CTIP2 is highly expressed in the thymus and mature T cells and they propose to study the role of this protein in T cell differentiation and function. Recently, it has been shown that dysfunctional expression of CTIP1 results in leukemia in mice. They expect that, similarly, dysfunction in expression of CTIP2 will affect normal differentiation and function of T cells.
The first aim of this proposal is to confirm that CTIP2 is a transcriptional modulator in T cells and identify target genes that are regulated by CTIP2 in T cells. Another goal is to determine what role CTIP2 plays during T cell development by studying the expression profiles of CTIP2 and its target genes during T cell differentiation. The next goal is to determine what role CTIP2 plays in resting and activated T cells and to decipher the mechanisms underlying the transcriptional regulation mediated by CTIP2. All these goals will be pursued under the direct mentoring and supervision of Dr. Anthony Vella and Dr. Mark Leid. Dr. Vella will supervise the candidate's training in immunology. Experiments addressing transcriptional regulation, gene expression, yeast two hybrid screening, cloning, etc. will be conducted in Dr. Leid's laboratory and under his supervision.
| Albu, Diana I; Feng, Dongyun; Bhattacharya, Debarati et al. (2007) BCL11B is required for positive selection and survival of double-positive thymocytes. J Exp Med 204:3003-15 |
| Cismasiu, Valeriu B; Adamo, Karen; Gecewicz, Jennifer et al. (2005) BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter. Oncogene 24:6753-64 |
| Avram, Dorina; Fields, Andrew; Senawong, Thanaset et al. (2002) COUP-TF (chicken ovalbumin upstream promoter transcription factor)-interacting protein 1 (CTIP1) is a sequence-specific DNA binding protein. Biochem J 368:555-63 |
