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Adults (18-65), Geriatrics (65+)
Adults (18-65), Geriatrics (65+)
Hospital of the University of Pennsylvania
3400 Spruce Street
Philadelphia, PA 19104
A facility of the Hospital of the University of Pennsylvania
Research Interests Tumor Biology, Development, Stem Cells, Hematopoiesis, Immune Function Research Techniques: In vivo and in vitro models of hematopoiesis, transformation and immunity, retroviral transduction, bone marrow transplantation, ES cell culture and differentiation, cDNA cloning, cell sorting, video microscopy, knockout and RNAi technology, ChIP-Seq and global transcription analysisDescription of ResearchA major area of interest of this laboratory is understanding the processes that lead to the development and differentiation of mature hematopoietic cells from a single hematopoietic stem cell. We are particularly interested in studying the processes that perturb these normal processes and cause leukemia. A primary focus of the laboratory is the role that Notch proteins play in regulating hematopoietic cell fate decisions and cancer. Notch proteins are a conserved family of receptors that regulate cell fate decisions in organisms ranging from Drosophila to humans. Using a variety of in vitro and in vivo approaches, we have shown that Notch proteins are key regulators of multiple hematopoietic cell fates. These include establishment of the T cell lineage and helper type 2 T cells. We are presently undertaking studies to identify the signaling pathways that control these and other cell fate decisions in hematopoiesis. In addition to their role in normal hematopoiesis, dysregulation of Notch signaling is a cause of human leukemia. We have developed a mouse model of Notch-related leukemia and are using this to study the signaling pathways that lead to oncogenic transformation. Using gene array and bioinformatics approaches, we have identified several direct transcriptional targets of Notch signaling that appear to mediate its effects in normal development and leukemia. In addition, we are developing and testing ways to block Notch signaling that may be useful in treating leukemia and other Notch-dependent diseases.Rotation Projects1. Characterization of Notch transcriptional targets in hematopoiesis and leukemia. This project will characterize potential direct transcriptional targets of Notch signaling that we have identified in a microarray screen. The project will involve verifying that these are direct transcriptional targets using chromatin immunoprecipitation (ChIP), EMSA, and reporter assays and then testing whether these targets are functionally important using retroviral transduction, apoptosis, proliferation, and differentiation in both primary and established cell lines. 2. Identification of genes that potentiate Notch transforming activity. We have induced a number of Notch T cell leukemias using retroviruses that express activated forms of Notch1. The retroviral vectors also contain enhancer elements that can activate transcription of genes in the vicinity of their integration site. We have established techniques to rapidly clone the genes that are activated by retroviral vector integration and will use both in vitro and in vivo assays to determine if they synergize with Notch to induce leukemia. 3. We have identified Tribbles as a novel oncogene in acute myelogenous leukemia. Very little is know about Tribbles function. This project will use biochemical and functional assays to determine the function of Tribbles in leukemia and normal hematopoietic development. Lab personnel: Katherine Forsyth, Graduate StudentEthan Mack, Graduate StudentVicki Mercado, Post-baccalaureate ScholarCaitlin O'Neill, Administrative AssistantYumi Ohtani, Senior Research InvestigatorJelena Petrovic, Postdoctoral FellowKelly Rome, Graduate StudentSarah Stein, Postdoctoral FellowLanwei Xu, Research Specialist/Lab Manager
Kobia FM, Preusse K, Dai Q, Weaver N, Hass MR, Chaturvedi P, Stein SJ, Pear WS, Yuan Z, Kovall RA, Kuang Y, Eafergen N, Sprinzak D, Gebelein B, Brunskill EW, Kopan R: Notch dimerization and gene dosage are important for normal heart development, intestinal stem cell maintenance, and splenic marginal zone B-cell homeostasis during mite infestation. PLoS Biol : 2020.
Rome Kelly S, Stein Sarah J, Kurachi Makoto, Petrovic Jelena, Schwartz Gregory W, Mack Ethan A, Uljon Sacha, Wu Winona W, DeHart Anne G, McClory Susan E, Xu Lanwei, Gimotty Phyllis A, Blacklow Stephen C, Faryabi Robert B, Wherry E John, Jordan Martha S, Pear Warren S: Trib1 regulates T cell differentiation during chronic infection by restraining the effector program. J. Exp. Med. 217 (5): 2020.
Schwartz Gregory W, Zhou Yeqiao, Petrovic Jelena, Fasolino Maria, Xu Lanwei, Shaffer Sydney M, Pear Warren S, Vahedi Golnaz, Faryabi Robert B: TooManyCells identifies and visualizes relationships of single-cell clades. Nature methods : 2020.
Zheng, Q, Capell B, Parekh V, O’Day C, Atillasoy C, Bashir HM, Eun-Hee S, Yeh C, Prouty S, Pear WS, Grice EA, Seykora JT: Whole exome and transcriptome analysis of UV-exposed epidermis and carcinoma in situ reveals early drivers of carcinogenesis J. Invest. Derm. : in the press,2020.
Petrovic J, Zhou Y, Fasolino M, Goldman N, Schwartz GW, Mumbach MR, Nguyen SC, Rome KS, Sela Y, Zapataro Z, Blacklow SC, Kruhlak MJ, Shi J, Aster JC, Joyce EF, Little SC, Vahedi G, Pear WS*, Faryabi RB*.: Oncogenic Notch Promotes Long-Range Regulatory Interactions within Hyperconnected 3D Cliques. Molecular Cell 73 (6): 1174-1190,2019.
Mack EA, Stein SJ, Rome KS, Xu L, Wertheim GB, Melo RC, Pear WS: Trib1 regulates eosinophil lineage commitment and identity by restraining the neutrophil program. Blood : 2019.
Guerrero-Juarez CF, Dedhia PH, Jin S, Ruiz-Vega R, Ma D, Liu Y, Yamaga K, Shestova O, Gay DL, Yang Z, Kessenbrock K, Nie Q, Pear WS, Cotsarelis G, Plikus MV.: Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds.Nature Nature Communications 10 (1): 2019.
Kong G, You X, Wen Z, Chang Y-I, Qian S, Ranheim E.A, Letson C, Zhang X, ZY, Liu Y, Rajagopalan A, Zhang J, Stieglitz E, Loh M, Hofmann I, Yang D, Zhong X, Padron E, Zhou L, Pear W.S., Zhang J: Downregulating Notch counteracts Kras-induced ERK activation and oxidative phosphorylation in myeloproliferative neoplasm. Leukemia : 2018.
Maillard, IM and Pear, WS: Can genetics resolve what Notch does in HSCs Blood : 2018.
Johnson JL, Georgakilas G, Petrovic J, Kurachi M, Cai S, Harly C, Pear WS, Bhandoola A, Wherry EJ, Vahedi G: Lineage-determining transcription factor TCF-1 initiates the epigenetic identity of T cells. Immunity 48 : 243-257,2018.
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