Challenge Grants

The following grants were awarded in 2013:

John Varga and Jonathan Licht, of Northwestern University "Adipocytes - the cell of origin of fibrosis in myeloproliferative neoplasm"
The PIs propose that adipocytes (fat cells) in the bone marrow respond to altered cytokine secretion in such a way that they increase production of fibroblasts and subsequent fibrosis. They use novel mouse models to study this process. They will also test whether an inhibitor of one pathway that controls adipogenesis can block fibrosis in an animal model. A strength of the grant is the new collaboration between Dr. Varga, who is an expert of pulmonary fibrosis and Dr. Licht who is an expert in hematopoiesis.

Golam Mohi, of State University of New York "Molecular mechanism of myelofibrosis induced by JAK2V617F"
This grant looks at the contribution of two genes to JAK2V617F activity in the MPNs. The genes include SHP2, a protein phosphatase that can both increase and decrease signaling in different contexts, and a transcription regulator named Bmi1. The study is expected to provide new insights into how genes cooperate to promote MPNs.

Emmanuele Passegue, of University of California at San Francisco
"Targeting the remodeling of the osteoblastic bone marrow niche by MPN myeloid cells to prevent myelofibrosis"
Dr. Passegué has recently shown that multi-potent stromal cells respond to cytokines secreted by MPN myeloid cells by converting to osteoblastic lineage cells (OBCs) in mouse models of CML. These altered OBCs drive an inflammatory process in the bone that she proposes leads to fibrosis. In this grant, she will study whether a similar phenomenon occurs in the MPNs by using the JAK2V617F and MPLW515L models.

Xiaoli Wang, of Mt. Sinai School of Medicine
"The role of thrombopoietin and its receptor in myelofibrosis"
Wang has recently shown that blood stem cells from the spleen of MF patients show an increased stem cell activity as compared to stem cells from peripheral blood. Despite showing improved blood cell activity in recipient mice, the mice do not show changes in megakaryocytes or develop myelofibrosis. She proposes to introduce human thrombopoietin (the cytokine that promotes megakaryocytes) into mice that are transplanted with MF splenic stem cells. She will also study the requirement for TPO in proliferation of MF cells and the disease in recipient mice. The significance of this proposal is that development of a more faithful mouse model of MF will improve our ability to study the biology of MF in vivo and test novel MF therapies.

The following grants were awarded in 2012:

Ann Mullaly & Benjamin L. Ebert, of Brigham & Women’s Hospital "Determination of the cytokines that are necessary and sufficient to include fibrotic transformation in JAK2V617F-mediated MPN"
The investigators will attempt to determine the cytokines that are necessary and sufficient to induce fibrotic transformation in JAK2V617F-mediated MPNs, using an in-vivo model of MF in a JAK2 knockin mouse they have recently developed. The information obtained will provide the basis for development of novel therapeutics for the treatment of MF patients, such as neutralizing antibodies and/or small molecules that inhibit key cytokine drivers of MF.

Amit Verma and Zhizhuang Joe Zhao, of the Albert Einstein College of Medicine and University of Oklahoma Health Sciences Center  "Efficacy of a clinically relevant TGF-Beta receptor kinase inhibitor in myelfibrosis"
This project will investigate the role of TGF-Beta as a mediator of fibrosis in PMF. As a first aim, they will determine the mechanisms of constitutive activation of TGF-Beta in bone marrow failure and will identify its downstream effectors, using bone marrow samples from patients with MF. As a second aim, they will assess the effectiveness of a specific TGF-Beta inhibitor on MF in a transgenic mouse model of MF, with the hope of setting the stage for trials of such inhibitors in MF patients.

Pearlie Epling-Burnette and Adam Mailloux, of the H. Lee Moffitt Cancer Center "Blockade in mesenchymal stromal self-renewal as a novel mediator of the profibrotic marrow phenotype"
This project will investigate the linkage between cellular senescence and fibrosis, and specifically whether TGF-Beta-induced senescence in bone marrow-derived mesenchymal stem cells (MSCs) is associated with increased collagen deposition, contributing to fibrosis in patients with MPNs. They will use both in-vitro and in-vivo models to focus specifically on the role of FGF2 secretion by MSCs, which induces senescence of MSCs characterized by decreasing proliferative capacity and increased collagen secretion. An understanding of these mechanisms will provide new therapeutic targets for MF and other fibrotic diseases.

C. Arnold Spek, of the Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam"Bone marrow fibrosis: proof of principle for a potential therapeutic role of protease activated receptor inhibitors"
This grant investigates the role of protease-activated receptors (PARs), the downstream effect of PARs on the coagulation system, and the consequent effect on bone marrow fibrosis in MF patients. PARs have been implicated in many other types of fibrosis (e.g., pulmonary fibrosis), but their role and effect in MF is not clearly understood. The investigators will study the effect of PARs in novel co-cultured systems of MF, which may provide a novel alternative model of disease exploration. Using this model system, they will also begin to test the effects of PAR inhibitors.

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