PROJECTS
Based on our interest in bone marrow failure and genomic instability, we are working on three related projects.
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We work on another rare blood disorder congenital dyserythropoietic anemia (CDA).
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As in FA, codanin, the protein whose gene is mutated in CDA has no known function, and additional genes accounting for additional genetic complementation groups remain to be cloned and identified. The work on CDA is performed in collaboration with collaborators such as Dr Diane Krause, Dr Patrick Gallagher, and Dr Sherman Weissman in the Yale Cooperative Center for Experimental Hematology. We have identified a novel role for codanin in erythroid differentiation via transcriptional control. Such work, while focused on a rare disorder, has the promise to confer insight into the normal processes of red cell production.
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We are investigating ways to use our knowledge of genomic instability for improving cancer therapeutics.
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We work with Dr Barbara Burtness, a prominent head and neck oncologist. FA patients are especially prone to head and neck tumors as adults, and non-FA patients' tumors have a high percentage of FA gene somatic mutations. Such genomic information suggests a therapeutic opening. We have identified several drugs that may hold promise in the treatment of such tumors and are working on these ideas in several experimental models.
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We have also started more clinical projects, using the same mass spectroscopy technology we have used to find FA binding proteins.
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Again in collaboration with the Semmes laboratory, we have adapted the mass spec to analyze sera from patients with pediatric malignancies, specifically Hodgkin lymphoma in order to identify unique protein markers of disease. These markers could then be used for diagnosis, prognosis, staging, and tracking of minimum residual disease in patients. In addition, our goal is to identify interesting proteins for further analysis in our laboratory.
Further, we have collected blood from 6 families in which there is a parent and child with Hodkgin lymphoma. We have utilized Next Generation DNA sequencing to identify a candidate gene for familial Hodgkin. We have already identified several exciting candidates and are in the process of further evaluation.
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Fanconi Amenia Protein Pathway
The Fanconi Anemia (FA) core complex localizes to chromatin during the S phase and in response to DNA damage. Within the core complex, both FANCA and FANCG are phosphorylated (P). In the presence of an intact core complex, FANCD2 is monoubiquitinated (Ub) on K561 and colocalizes in nuclear foci with BRCA1, where it carries out its roles in DNA repair and/or cell cycle control. FANCD2 is a phosphorylation target of kinases ATM and perhaps ATR, a phosphorylation that is necessary to maintain the S-phase checkpoint. At mitosis, FANCG is phosphorylated, and the core complex is excluded from the nucleus and condensed chromatin.