Notch signaling regulates multiple aspects of hematopoietic development. Notch receptors are a conserved family that influence cell fates, survival, proliferation, and border formation in multi-cellular organisms. This competing renewal represents our long-term plan to understand the function of Notch signaling in hematopoietic development and function. We and others have provided evidence that Notch regulates T cell commitment from a multi-potential progenitor and regulates multiple aspects of intrathymic T cell development, The proposed studies focus on the function of Notch signaling in T cell commitment and early thymocyte development, In Specific Aim 1, we will identify the bone marrow, intra-thymic and extra-thymic progenitors upon which Notch acts to specify T cell commitment.
In Specific Aim 2, we will determine the function of Notch signaling and identify the mechanism by which Notch influences multiple events during early thymocyte development.
In Aim 3, we will determine the mechanism that downregulates Notch signaling at the DN3-DN4 transition. Our studies will utilize a combination of murine models, including a novel loss-of-function model created by us, organ and stromal cell cultures, and biochemical approaches. In particular, we seek to understand the function of Notch signaling at the pre-TCR checkpoint, the downstream signals by which Notch regulates intrathymic T cell development, and the mechanisms regulating Notch1 transcription. Together, these studies will lead to an improved understanding of lymphocyte development and function, and in doing so, will provide insights into modulating the immune system for therapeutic advances. ? ?
| Johnson, John L; Georgakilas, Georgios; Petrovic, Jelena et al. (2018) Lineage-Determining Transcription Factor TCF-1 Initiates the Epigenetic Identity of T Cells. Immunity 48:243-257.e10 |
| Plikus, Maksim V; Guerrero-Juarez, Christian F; Ito, Mayumi et al. (2017) Regeneration of fat cells from myofibroblasts during wound healing. Science 355:748-752 |
| Ryan, Russell J H; Petrovic, Jelena; Rausch, Dylan M et al. (2017) A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas. Cell Rep 21:784-797 |
| Pajcini, Kostandin V; Xu, Lanwei; Shao, Lijian et al. (2017) MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia. Sci Signal 10: |
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| Uljon, Sacha; Xu, Xiang; Durzynska, Izabela et al. (2016) Structural Basis for Substrate Selectivity of the E3 Ligase COP1. Structure 24:687-696 |
| Stein, Sarah J; Mack, Ethan A; Rome, Kelly S et al. (2016) Trib2 Suppresses Tumor Initiation in Notch-Driven T-ALL. PLoS One 11:e0155408 |
| Basu, Rajatava; Whitley, Sarah K; Bhaumik, Suniti et al. (2015) IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell-iTreg cell balance. Nat Immunol 16:286-95 |
| Stein, Sarah J; Mack, Ethan A; Rome, Kelly S et al. (2015) Tribbles in normal and malignant haematopoiesis. Biochem Soc Trans 43:1112-5 |
| Yashiro-Ohtani, Yumi; Wang, Hongfang; Zang, Chongzhi et al. (2014) Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia. Proc Natl Acad Sci U S A 111:E4946-53 |
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