This application is submitted by an individual with previous research experience in toxicology and clinical training in pathology. The applicant is committed to pursue a career as a physician scientist focusing on molecular pathology. It is therefore necessary for the applicant to receive further training in molecular biology and immunology. The applicant will be mentored by Dr. Xiao-Hong Sun at New York University School of Medicine. The proposed research project attempts to address the mechanism by which the basic helix-loop-helix (bHLH) transcription factors, E proteins, control T cell development and prevent T cell lymphomagenesis. The crucial roles of E proteins in T cell development and tumor suppression has recently been demonstrated in Dr. Sun's laboratory by using a transgenic mouse model, in which the Id1 gene, encoding a natural dominant- negative inhibitor of all E proteins, is expressed specifically in the T cell lineage. T cell development in these mice is blocked at the progenitor stage and T cell lymphoma appears in adult mice at a high frequency. To elucidate the underlying mechanisms, I hypothesize that excessive apoptosis of differentiating T cells prevents the accumulation of viable differentiating T cells, and thus dramatically reduces the cellularity in the thymus. I propose that the reasons for the aberrant apoptosis may be due to inappropriate V(D)J recombination of the T cell receptor (TCR) genes such as the incorrect timing at which recombination occurs and the inefficiency at which the rearranged fragments are joined. The inappropriate recombination events may then trigger DNA-damage mediated apoptosis. Increased apoptosis may also take place as a result of the failure to support progenitor cell survival during early stages of differentiation. To test this hypothesis, I will cross the Id1 transgenic mice with RAG 1-/-, p53-/- or bc12 transgenic mice, which will prevent inappropriate recombination, impair DNA-mediated apoptosis and enhance cell survival, respectively. T cell development and lymphomagenesis in these hybrid mice will then be analyzed in comparison with the Id1 transgenic mice as well as RAG1-/-, p53-/- or bc12 transgenic mice. In this proposal, I have also outlined experiments investigating the mechanisms concerning lymphoma development and progression. I belief that knowledge that I will acquire regarding normal T cell development will shed light on the mechanism of lymphomagenesis. It is interesting to determine if the block of T cell development and the predisposition of lymphoma share any common mechanisms. Through these studies, I plan to acquire the knowledge and skills in the fields of molecular biology and immunology and develop my own independent research program.
