Dr. Clapp's laboratory is focused on understanding the molecular pathogenesis of two genetic diseases that result in both hematopoietic malignancies as well as solid tumors. One major area of interest is to understand the role of the NF1 tumor suppressor gene. Mutations in NF1 cause the common genetic disorder neurofibromatosis type 1 (NF1) which is associated with a predisposition to neural crest derived tumors and juvenile myelomonocytic leukemia (JMML). Neurofibromin, the protein product of the NF1 gene, functions at least in part as a GTPase activating protein that regulates Ras proteins by stimulating their intrinsic GTPase activity. Haploinsufficiency of NF1, via its role in lineages of the tumor microenvironment, is becoming increasingly recognized for its involvement in tumor progression in malignancies affecting individuals with NF1. Dr. Clapp's laboratory provided the first genetic evidence that haploinsufficiency of NF1 alters cell fates in lineages implicated in the disease pathogenesis of neurofibromatosis type 1. Subsequent work identified a mechanism for how mast cells are recruited to the emerging tumor microenvironment. Most recently he and his collaborators have demonstrated a key role for the hematopoietic system and the c-kit/kit ligand pathway in plexiform neurofibroma tumor progression. These results have led to a phase 2 clinical trial currently in progress under the direction of Dr. Kent Robertson. Ongoing work is focused on both understanding additional paracrine interactions in the growth of plexiform neurofibromas and in identifying additional molecular targets involved in tumor progression.
Dr. Clapp's group is also interested in the cellular and biochemical functions of an orphan group of proteins that are involved in the heterogenetic disorder Fanconi Anemia. Fanconi anemia (FA) is a rare heterogeneous genetic disorder composed of at least 13 complementation groups. The disease is characterized by a progressive bone marrow aplasia, chromosomal instability, hypersensitivity to bi-functional alkylating agents and the acquisition of malignancies, including a high predisposition for hematopoietic malignancies. Dr. Clapp's laboratory is focusing on understanding the molecular mechanisms that underlie the genesis of the bone marrow failure and clonal evolution of hematopoietic malignancies. Investigators in his lab have recently generated unique murine models to address these questions. A second area of emphasis is in the development of gene transfer and transplantation protocols to optimize gene transfer and engraftment of FA deficient cells using murine models. Dr. Clapp and his collaborators are currently developing modified foamyviral and lentiviral vector delivery systems that appear to have several advantages over traditional retroviruses.
