Faculty

D. Wade Clapp, MD

D. Wade Clapp, MD

Assistant: Heather Daniel
Phone: (317) 278-9290
Email: hdaniel@iu.edu
Address:
1044 W Walnut Street, R4/402B
Indianapolis, IN 46202

Bio

Specialty

Neonatology

Areas of Interest

Understand the molecular pathogenesis of two genetic diseases that result in malignancies and tumors, with a focus in the role of the NF1 tumor suppressor gene. Study the cellular and biochemical functions of the disorder Fanconi anemia.

D. Wade Clapp, M.D., is the Richard L. Schreiner Professor and Chairman, Department of Pediatrics. He is also Physician-in-Chief for Riley Hospital for Children and a Professor; Microbiology & Immunology/Biochemistry & Molecular Biology.

Education

1977 B.A., Hanover College
1982 M.D., Indiana University School of Medicine
1986 Resitent-Pediatrics, Indiana University School of Medicine
1989 Fellow-Neonatology, Case Western University, Cleveland, OH
1990 Research Fellow, Ireland Cancer Center, Case Western University, Cleveland, OH

Honors & Awards

1977 Outstanding Scholarship - Leadership Award, Hanover College
1982 Departmental Senior Honors - Pediatrics
1990-1991 Young Investigator Award, Rainbow Babies and Children's Hospital
1992 Clinical Investigator Award, Heart, Blood Institute-NIH
1992 Basil O'Connor Award - National March of Dimes Foundation
1997 Award of Tenure, Indiana University
2009 Clarian Presidential Award
2013 Glenn Irwin Research Award

Clinical


Research & Grants

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.

Current Grants

1. Neurofibromatosis Type 1 Gene Regulates Myelopoiesis, R01, NIH/NCI, PI

2. Fanconi Anemia Stem Cells Allow Molecular Characterization of Acute Leukemia, R01, NIH/NCI, Co-PI

3. Role of hematopoietic microenvironment in plexiform neurofibroma progression, P50, NIH/NINDS/UTS, PI for Project 2

4. Genetic Therapy for Fanconi Anemia, R01, NIH/NCI, Multi-PI

5. Cooperative Multicenter Neonatal Research Network, U10, Eunice Kennedy Shriver NIH/ NICHD, Neonatal Collaborator

6. Drug Discovery Initiative Neurofibromatosis Preclinical Consortium, Children’s Tumor Foundation, PI

7. Generation and initial characterization of an NF2 model that develops intracranial vestibular Schwannomas and meningiomas, DOD, PI

8. Neurofibromatosis Clincial Trials Consortium, DOD/UAB, PI

9. Experimental Therapeutics targeting the NF2 kinome: an integrated rational approach, CTF, PI

10. Testing the Pharmacologic and genetic role of P21 activated kinase inhibtion on Schwannoma Formation using a Novel Genetically Engineered Murine Mouse model that Closely Phenocopies Human NF2 Disease, DOD, co-PI.


Representative PublicationsView All Publications

1. Ingram, D.A., Hiatt, K., King, A.J., Fisher, L., Shivakumar, R., Derstine, C., Wenning, M.J., Diaz, B., Travers, J.B., Hood, A., Marshall, M., Williams, D. A., Clapp, D. W., ., Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. J Exp Med, 2001. 194(1): p. 57-69. PMCID: 2193446.

2. Ingram DA, Wenning MJ, Shannon K, Clapp DW. Leukemic potential of doubly mutant Nf1 and Wv hematopoietic cells. Blood 2003 101(5):1984-1986. PMID: 12393498

3. Yang FC, Ingram DA, Chen S, Li X, Clegg TE, White H, Mead L, Atkinson S, Kapur R, Williams DA, Clapp DW. Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1 +/- mast cells. J Clin Invest. 2003 112:1851-1861. PMCID: PMC296994

4. Yang FC, Chen S, Clegg T, Li X, Morgan T, Estwick S, Yuan J, Khalaf W, Burgin S, Travers J, Parada LF, Ingram DA, Clapp DW. Nf1+/- mast cells induce neurofibroma like phenotypes through secreted TGF-? signaling. Hum Mol Gen 2006 15(16): 2421-2437. PMCID: PMC3024714

5. Yang FC, Chen S, Nebesio TD, Morgan T, Li X, Yuan J, Hock J, Ingram DA, Clapp DW. Haploinsufficiency of Nf1 alters Ras-Pl3K activity in osteoclasts cell fates in vitro and in vivo. J Clin Invest. 2006 116: 2880-2891. PMCID: PMC1616197 6. Yang FC, Ingram DA, Chen S, Xiaohong L, Morgan T, Yuan J, Hutchins G, Parada L, Clapp DW. Nf1-Dependent Tumors Require a Microenvironment Containing Nf1+/- and c-kit-Dependent Bone Marrow. Cell 2008 Oct 31;135(3):437-48. PMCID: PMC2788814

7. McDaniel AS, Allen JD, Park SJ, Jaffer ZM, Michels EG, Burgin SJ, Chen S, Bessler WK, Hofmann C, Ingram DA, Chernoff J, Clapp DW. Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/- mast cells. Blood 2008 Dec 1; 1112(12):4646-54. Epub 2008 Sep 2. PMCID: PMC2597131 8. Si Y, Linka Y, Ciccone S, Leurs C, Yuan J, Eckermann O, Fruehauf S, Hanenberg H, Clapp DW. Overnight transduction with foamyviral vectors restores the long-term repopulating activity of Fancc-/- stem cells. Blood 2008 Dec 1;112(12):4458-65. Epub 2008 Aug 6. PMCID: PMC2597121

9. Allen, JD, Jaffer, ZJ, Park, SJ, Burgin, S, Hofmann, C, Sells, MA, Chens, S, Derr-Yellin, E, Michels EG, Bessler, WK, Ingram, DA, Atkinson, SJ, Travers, JB, Chernoff,, J, and Clapp, DW. P21-Activated Kinase Regulates Mast Cell Degranulation Via Effects on Calcium Mobilization and Cytoskeletal Dynamics. Blood 2009 Mar 19;113(12):2695-705. Epub 2009 Jan 5. PMCID: PMC2661857

10. Staser K, Yang FC, Clapp DW. Mast cells and the neurofibroma microenvironment. Blood 2010 Jul 15;116(2):157-64 PMCID: 2910605; PMCID: PMC3182976

11. Staser K, Yang FC, Clapp DW. Plexiform neurofibroma genesis: questions of Nf1 gene dose and hyperactive mast cells. Curr Opin Hematol. 2010 Jul;17(4):287-93. PMCID: PMC3539783

12. Chen S, Burgin S, McDaniel A, Li X, Yuan J, Chen M, Khalaf W, Clapp DW, Yang FC. Nf1-/- Schwann cell-conditioned medium modulates mast cell degranulation by c-Kit-mediated hyperactivation of phosphatidylinositol 3-kinase. Am J Pathol. 2010 Dec;177(6):3125-32. Epub 2010 Oct 29. PMCID: PMC2993306.

13. Chen M, Burgin S, Staser K, He Y, Li X, Robinson M, Jiang L, Chan RJ, Ingram D, Clapp DW. Kinase suppressor of Ras (KSR1) modulates multiple kit-ligand-dependent mast cell functions. Exp Hematol. 2011 Oct;39(10):969-76. PMCID: PMC3182112

14. Wu X, Chen S, He Y, Rhodes SD, Mohammad KS, Li X, Yang X, Jiang L, Nalepa G, Snider P, Robling AG, Clapp DW, Conway SJ, Guise TA, Yang FC. The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1. PLoS One. 2011;6(9):e24917. Epub 2011 Sep 29. PMCID: PMC3182976.

15. Wang Z, Oh E, Clapp DW, Chernoff J, Thurmond DC. Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo. J Biol Chem. 2011 Oct 3. PMCID: PMC3308848

16. Staser K, Yang FC, Clapp DW. Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression. Annu Rev Pathol. 2012;7:469-95. Epub 2011 Nov 7. PubMed PMID: 22077553. PMCID: PMC369473816. Staser K, Park S, Rhodes S, Zeng Y, He YZ, Shew M, Gehlhausen J, Cerabona D, Chen S, Sun Z, Nalepa G, Yang FC, Clapp DW. Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk. J Clin Invest. 2013 Jan 2;123(1):329-34. doi: 10.1172/JCI66167. Epub 2012 Dec 10. PMCID: PMC3533306

17. Robertson K, Nalepa G, Yang FC, Bowers D, Ho C, Hutchins G, Croop J, Vik T, Denne S, Parada L, Hingtgen C, Walsh L, Yu M, Pradhan K, Edwards-Brown M, Cohen M, Fletcher J, Travers J, Staser K, Lee M, Sherman M, Davis C, Miller L, Ingram D, Clapp DW. Imatinib mesylate for plexiform neurofibromatosis in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol. 2012 Dec;13(12):1218-24. doi: 10.1016/S1470-2045(12)70414-X. Epub 2012 Oct 23. PMID:23099009 [PubMed - indexed for MEDLINE]

18. Staser K, Shew MA, Michels EG, Mwanthi MM, Yang FC, Clapp DW, Park SJ. A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells. Exp Hematol. 2013 Jan;41(1):56-66.e2. doi: 10.1016/j.exphem.2012.10.001. Epub 2012 Oct 11. PMCID: PMC23063725

19. Nalepa G, Barnholtz-Sloan J, Enzor R, Dey D, He Y, Gehlhausen J, Lehmann A.S., Park S, Yang Y, Yang X, Chen S, Guan X, Yanwen C, Renbarger J, Yang FC, Parada L, Clapp DW. The Tumor Suppressor CDKN3 Controls Mitosis. JCB. 2013 Jun 24;201(7):997-1012. doi: 10.1083/jcb.201205125. Epub 2013 Jun 17. PMCID: PMC3691455 [Available on 2013/12/24].

20. Nalepa G, Enzor R, Sun Z, Marchal C, Park SJ, Yang Y, Tedeschi L, Hanenberg H, Clapp DW. Fanconi anemia signaling network regulates the spindle assembly checkpoint. JCI. 2013 Sep 3;123(9):3839-47. doi: 10.1172/JCI67364. Epub 2013 Aug 15. PMCID: PMC3754252.