MF Challenge 2012 Grant Recipients

Ann Mullaly & Benjamin L. Ebert, of Brigham & Women’s Hospital 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 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-Burnett and Adam Mailloux, of the H. Lee Moffitt Cancer Center 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 will investigate 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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