D. Wade Clapp, M.D.
Richard L. Schreiner Professor and Chairman, Department of Pediatrics
Physician-in-Chief, Riley Hospital for Children at Indiana University Health
Professor, Microbiology & Immunology; Biochemistry & Molecular Biology
Indiana University School of Medicine
Herman B. Wells Center for Pediatric Research
M .D. Indiana University, Indianapolis, IN (1982)
My laboratory is focused on studying the molecular pathogenesis of neurofibromatosis type 1 (NF1). NF1 is caused by mutations of the NF1 tumor suppressor gene that functions as a GTPase activating protein for p21Ras. Individuals with NF1 have a high predisposition to neural crest derived tumors called plexiform neurofibromas. Plexiform neurofibromas are congenital in origin, arise from large peripheral and cranial nerves and are resistant to radiation and chemotherapy. A key goal of our laboratory is to conduct studies to elucidate key pathological cell-cell and hyperactive Ras-mediated signaling pathways using a genetically engineered murine model that closely recapitulates the steps in plexiform neurofibroma formation in humans. Given the intractability of targeting Ras directly, our laboratory has to date focused on genetically disrupting components of the Ras pathway, both using mouse genetics and subsequently by pharmacologic inhibition. Molecular targets that are identified as having a significant therapeutic effect are then moved forward into phase 1 and phase 2 clinical trials. Positions that I hold in preclinical and clinical consortiums facilitate the translation of this basic work.
- Gehlhausen JR, Park SJ, Hickox AE, Matthew S, Staser K, Rhodes SD, Menon K, Lajiness JD, Mwanthi M, Yang X, Yuan J, Territo P, Hutchins G, Nalepa G, Yang FC, Conway SJ, Heinz MG, Stemmer-Rachamimov A, Yates CW, Clapp DW. A murine model of Neurofibromatosis Type 2 that accurately phenocopies human schwannoma formation. Hum Mol Genet. 2014. pii: ddu414. [Epub ahead of print]. PMID: 25113746 [PubMed – as supplied by publisher]- in press.
- De Raedt T, Beert E, Pasmant E, Luscan A, Brems H, Ortonne N, Helin K, Hornick JL, Mautner V, Kehrer-Sawatzki H, Clapp W, Bradner J, Vidaud M, Upadhyaya M, Legius E, Cichowski K. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD-4 based therapies. Nature. 2014 – in press.
- Molosh A, Johnson PL, Spence JP, Arendt D, Federici LM, Bernabe C, Janaski SP, Segu ZM, Khanna R, Goswami C, Zhu W, Li L, Mechref YS, Clapp DW, Shekhar, A. Social learning deficits in Neurofibromatosis type 1 are linked to disruptions of network functions and synaptic proteins in the amygdala and can be rescued by blocking p21-activated kinase 1 function. Nature Neurosci. 2014 – in press.
- Widemann BC, Acosta MT, Ammoun S, Belzberg AJ, Bernards A, Blakeley J, Bretscher A, Cichowski K, Clapp DW, Dombi E, Evans GD, Ferner R, Fernandez-Valle C, Fisher MJ, Giovannini M, Gutmann DH, Hanemann CO, Hennigan R, Huson S, Ingram D, Kissil J, Korf BR, Legius E, Packer RJ, McClatchey AI, McCormick F, North K, Pehrsson M, Plotkin SR, Ramesh V, Ratner N, Schirmer S, Sherman L, Schorry E, Stevenson D, Stewart DR, Ullrich N, Bakker AC, Morrison H. CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies. Am J Med Genet A. 2014 Mar;164A(3):563-78. PMID: 24443315 [PubMed – in process].
- Li F1, Downing BD, Smiley LC, Mund JA, Distasi MR, Bessler WK, Sarchet KN, Hinds DM, Kamendulis LM, Hingtgen CM, Case J, Clapp DW, Conway SJ, Stansfield BK, Ingram DA Jr. Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. Circulation. 2014 Mar 18;129(11):1213-24. PMCID: PMC3960343.