D. W. Clapp, MD
Chair, Department of Pediatrics
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. Dr. Clapp was named Chair of Pediatrics in September 2009. He is a neonatologist and a physician/scientist with an active lab and NIH grant support focusing on translational research. His research has been internationally acclaimed and has resulted in several clinical trials. He is also past director of the MD/PhD program at IU which is now an NIH designated Medical Scientist Training Program
705 Riley Hospital Drive Rm 5900
Indianapolis, IN 46202
Titles & Appointments
- Richard L. Schreiner Professor of Pediatrics
- Professor of Microbiology & Immunology
- Professor of Biochemistry & Molecular Biology
Our laboratory focuses on the molecular pathogenesis of neurofibromatosis type 1 and neurofibromatosis type 2. Neurofibromatosis type 1 is the most common genetic disease with a predisposition to cancer and one of a series of developmental disorders called Rasopathies that have a range of malignant, neurodevelopmental and other non-malignant disease manifestations. A major effort in the laboratory is understanding the genetic, biochemical and cell-cell interactions that lead to the genesis and progression of plexiform neurofibromas that are often congenital in origin and become clinically apparent in babies and young children. To elucidate key pathological cell-cell and hyperactive Ras-mediated signaling pathways we utilize a genetically engineered murine model that closely recapitulates the steps in plexiform neurofibroma formation in humans that was originally developed by Dr. Luis Parada and students in his laboratory. 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 have been identified in the lab as having a significant therapeutic effect are then moved forward into phase 1 and phase 2 clinical trials and an FDA RO1 sponsored clinical trial began in 2015. The drug discovery work has been supported with support from NINDS via a UO1 mechanism, in the context of a preclinical consortium of investigators supported by Neurofibromatosis Therapeutics Acceleration Program (NTAP) and the Children’s Tumor Foundation (CTF) and a SPORE application that will start this fall. Three drug targets tested in our preclinical model have now moved forward to the clinic. Our efforts in neurofibromatosis type 2 are more recent. Building on the novel Nf2flox/flox mouse originally developed by Dr. Marco Giovannini, we have generated a murine model that accurately recapitulates the genesis of human vestibular and paraspinal schwannomas with 100% penetrance. Much like the efforts in NF1, we are utilizing the model in part to better understand the molecular pathogenesis of schwannoma formation. In addition, we are collaborating with other investigators in a multi-investigator initiative focused on identifying novel experimental therapeutics (Synodos) sponsored by the Children’s Tumor Foundation.
Spatially- and temporally-controlled postnatal p53 knockdown cooperates with embryonic Schwann cell precursor Nf1 gene loss to promote malignant peripheral nerve sheath tumor formation.
Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial.
Inhibition of p21 activated kinase (PAK) reduces airway responsiveness in vivo and in vitro in murine and human airways.
The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1.
Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo.
Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression.
Nf1-/- Schwann cell-conditioned medium modulates mast cell degranulation by c-Kit-mediated hyperactivation of phosphatidylinositol 3-kinase.
Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia.
p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics.
Overnight transduction with foamyviral vectors restores the long-term repopulating activity of Fancc-/- stem cells.
Nf1+/- mice have increased neointima formation via hyperactivation of a Gleevec sensitive molecular pathway.
K-ras is critical for modulating multiple c-kit-mediated cellular functions in wild-type and Nf1+/- mast cells.
Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions.
Continuous in vivo infusion of interferon-gamma (IFN-gamma) enhances engraftment of syngeneic wild-type cells in Fanca-/- and Fancg-/- mice.
Stimulus-evoked release of neuropeptides is enhanced in sensory neurons from mice with a heterozygous mutation of the Nf1 gene.
Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist.
Continuous in vivo infusion of interferon-gamma (IFN-gamma) preferentially reduces myeloid progenitor numbers and enhances engraftment of syngeneic wild-type cells in Fancc-/- mice.
Fanconi anemia type C-deficient hematopoietic stem/progenitor cells exhibit aberrant cell cycle control.
Stromal cell-derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and G(alpha)i proteins and enhances engraftment of competitive, repopulating stem cells.
Transgenic expression of stromal cell-derived factor-1/CXC chemokine ligand 12 enhances myeloid progenitor cell survival/antiapoptosis in vitro in response to growth factor withdrawal and enhances myelopoiesis in vivo.
Enforced expression of CUL-4A interferes with granulocytic differentiation and exit from the cell cycle.
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.
Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo.
Cell cycle-related changes in repopulating capacity of human mobilized peripheral blood CD34(+) cells in non-obese diabetic/severe combined immune-deficient mice.
Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines.
Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac-/- mice.
Variation in long-term engraftment of a large consecutive series of lambs transplanted in utero with human hematopoietic cells.
The highest concentration of primitive hematopoietic progenitor cells in cord blood is found in extremely premature infants.
Molecular evidence that in situ-transduced fetal liver hematopoietic stem/progenitor cells give rise to medullary hematopoiesis in adult rats.
The use of umbilical cord blood as a cellular source for correction of genetic diseases affecting the hematopoietic system.
Rapid exit from G0/G1 phases of cell cycle in response to stem cell factor confers on umbilical cord blood CD34+ cells an enhanced ex vivo expansion potential.
Stable integration of retrovirally transduced genes into human umbilical cord blood high-proliferative potential colony-forming cells (HPP-CFC) as assessed after multiple HPP-CFC colony replatings in vitro.
Human umbilical cord blood hematopoietic progenitor cells: are they the same as their adult bone marrow counterparts?
Ex vivo expansion of CD34+ cells from purified adult human bone marrow and umbilical cord blood hematopoietic progenitor cells.
High efficiency retroviral mediated gene transduction into single isolated immature and replatable CD34(3+) hematopoietic stem/progenitor cells from human umbilical cord blood.
American Pediatric Society
American Society for Clinical Investigation
American Society of Clinical Oncology
American Society of Hematology
Association of Medical School Pediatric Department Chairs
International Society for Experimental Hematology
Society for Developmental Biology
Society for Pediatric Research
American Board of Pediatrics - Pediatrics
Desc: Trustee Teaching Award
Org: Alpha Omega Alpha Medical Honor Society
Desc: Alpha Omega Alpha