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2006 Young Investigator Award Recipients
2006 Postdoctoral Awardees
Jessica Casaletto, Ph.D.: Harvard Medical School/Massachusetts General Hospital
Role of Merlin and Ezrin in Junctional Remodeling during Tumorigenesis and Metastasis
This project addresses an important area of NF2 research: the relationship between merlin and the related ERM (Ezrin, Radixin, Moesin) proteins in epithelial tissues. Merlin is closely related to the ERM proteins, which localize to the cell membrane and regions of cell-cell contact, indicating roles in cell-cell communication. This project will study the balance of relationship between Merlin and Ezrin in morphogenesis and tumor progression. These studies will use Nf2 mutant mice and cells and will help to broaden our knowledge of the nature and function of merlin protein, which is essential in making progress toward developing therapeutics for NF2.
Chengkai Dai, Ph.D.: Massachusetts Institute of Technology
Role of Heat Shock Factor 1 (Hsf1) in modifying NF1-assiociated tumorigenesis
Given that NF1 is a progressive disease with a wide variability of clinical manifestations, it is likely that factors in addition to Nf1 gene mutations might profoundly modify the disease outcome. To provide better treatments and prognosis for NF1, it is important to identify those potential factors and understand the underlying mechanisms. This research is investigating the potential role in NF1 for Hsf1, a ‘master regulator’ of stress response in human disease and a crucial candidate modifier of tumor formation. It is hoped that these studies will provide not only basic mechanistic insights into how Hsf1 impacts NF1 disease outcomes, but also that they will be the basis for developing novel Hsf1-targeted therapeutics for NF1.
Ernesto Diaz-Flores, Ph.D.: University of California, San Francisco
Dissecting aberrant ras signaling induced by NF1 inactivation in myeloid disease
Clinical manifestations of NF1 include pediatric leukemias for which there are no effective current treatments. This research will use mouse models of Nf1- associated myeloid malignancies to study & uncover the signaling pathways alterations that contribute to these malignancies. This research will also use these models to address how inhibiting specific targets might represent candidate therapeutic approaches. This research will inform rational approaches to drug discovery and treatment, and potentially help to develop therapies for a broad range of NF1-derived tumors, as well as for myeloproliferative diseases and acute leukemia.
Cory Johannessen, Ph.D.: Harvard Medical School/Brigham & Women’s Hospital
Inhibition of the mTOR pathway as a therapy for NF1
The Nf1 gene product neurofibromin is a negative regulator of Ras (an important modulator of cell growth). However when neurofibromin is dysfunctional as it is in NF1, the precise pathways downstream of Ras that cause the clinical manifestations associated with NF1 are unclear. One of these, the mTOR pathway, is hyperactivated in tumor cells from patients with NF1. This research program will utilize mouse models of NF1 to explore mTOR inhibition as a therapeutic approach to treatment of NF1 tumors.
Jeong-Soo Lee, Ph.D.: Harvard University
Modeling NF1 and identifying its modifier using Zebrafish
Zebrafish are widely used to study genetic diseases & disorders. Unique advantages of zebrafish are the fact that they are easy to breed and study, and that many zebrafish genes are known to be similar in structure & function to human genes, so research findings from zebrafish can readily be translated to humans. This research project will be the first to study NF1 in zebrafish.
Zebrafish with mutations or blocked function in the Nf1 gene will be generated, to model the loss of gene function in NF1 patients. Mutant zebrafish will be analyzed to see which part of the NF1 protein is responsible for specific pathological abnormalities in different tissue types, and to begin to understand how the loss of NF1 results in such diverse symptoms in different NF1 patients. It will include a ‘modifier screen’ to help understand the complex molecular pathways controlled by the Nf1 gene, and identify new potential drug targets that can be used for the development of candidate NF1 therapeutics.
2006 Pre-doctoral Awardees
Monica Buchanan (Ph.D. candidate): Baylor College of Medicine
Localization of NF1-dependent learning in drosophila
This research project will study NF1-associated learning disabilities using Drosophila melanogaster - the fruit fly - as a model. The fruit fly is a widely used genetic model, and has previously been demonstrated as a useful model for such study of NF1-associated behavioral changes. The fly Nf1 gene is very similar to the human Nf1 gene, and genetically modified flies with disruptions in the Nf1 gene can readily be generated. A battery of meaningful behavioral tests can be used to test the behavioral impact on the flies of genetic modifications to the Nf1 gene. These studies will help to unravel the molecular processes involved in learning and memory and how these are impacted by individual Nf1 gene mutations.
Angela Hadjipanayis (Ph.D. candidate): University of Florid
Juvenile myelomonocytic leukemia (JMML) and other leukemias can affect children with NF1
JMML and related leukemias seen in NF1 are usually fatal. As is the case with NF1 solid tumors, there is a great need for therapeutics that can target the tumor cells without harming normal cells. This project is investigating a new gene that might be involved in the causal events of NF1 related leukemias. By unraveling this gene’s function in human leukemia samples and NF1 mouse and cell models, this research might offers a new target for developing better therapies for JMML and related leukemias, and potentially other NF1-related tumors.
Georgette Jones (Ph.D. candidate): Ohio State University
Investigating a role for The Carney Complex Gene PRKAR1A in NF1 and NF2 tumor formation
Schwann cells support and insulate nerve fibers throughout the body. However in NF1 and NF2, Schwann cells can give rise to schwannomas. These are usually benign but can become malignant. Schwannomas are also a feature of Carney Complex (CNC), which is caused by mutations in the gene PRKAR1A, an important regulator of the Protein Kinase A (PKA) pathway. This research will explore whether PRKAR1A also regulates schwannomas in NF1 and NF2. Tumors from a Prkar1a mouse model will be compared to NF1 and NF2 schwannomas. Interactions between PKA, neurofibromin and merlin will be studied. These studies could shed further light on the mechanisms of Schwann cell derived tumors in NF1 and NF2; demonstrate a role for PKA signaling pathway in NF1 or NF2; and delineate PKA as a candidate drug target for the treatment ofNF1 and NF2.
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