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Section of Neonatology, Perinatal and Pulmonary Biology

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Timothy E. Weaver, Codirector in the division of Pulmonary Biology at Cincinnati Children's Hospital Medical Center.

Timothy E. Weaver, MS, PhD

Title

Co-Director, Division of Pulmonary Biology

Appointment

Professor of Pediatrics, University of Cincinnati College of Medicine

Email

tim.weaver@cchmc.org

Phone

513-636-7223

Fax

513-636-7868

Bio

The goals of Dr. Timothy Weaver's work are to understand the structural basis for surfactant protein function and to identify the roles of these proteins in lung development and postnatal pulmonary physiology. These goals are achieved by expressing mutated/deleted surfactant protein transgenes in knockout mice and evaluating pathophysiologic changes associated with a specific mutation or loss of functional domain.

Dr. Weaver is a recipient of the prestigious MERIT award from the National Institutes of Health, NIH, and his research is supported by multiple grants from the NIH.

Profile

Read a profile about Dr. Weaver and the work he does in the Fall 2003 issue of Research Highlights. Read the article

Credentials

BS: Biology, Bob Jones University, Greenville, South Carolina, 1975

MS: Embryology, Hahnemann Medical College, Philadelphia, Pennsylvania, 1979

PhD: Developmental Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 1983

Postdoc: Molecular Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 1986

Position History

PAST POSITION: Assistant Professor of Pediatrics; Assistant Professor of Anatomy and Cell Biology, University of Cincinnati College of Medicine and Children’s Hospital Research Foundation, 1986-1990; Associate Professor of Pediatrics (tenured), University of Cincinnati College of Medicine and Children's Hospital Research Foundation 1990-1998.

PRESENT POSITION: Co-Director, Division of Pulmonary Biology, Children's Hospital Research Foundation, 2003-; Professor of Pediatrics (tenured), University of Cincinnati College of Medicine; Professor of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 1998-present.

Awards and Honors

  • MERIT Award, National Heart, Lung and Blood Institute, 2001-2011
  • Lung Biology and Pathology Study Section, 1995-1999
  • Site visitor/ad hoc reviewer for NHLBI, NIDDK, NICHD and NIEHS, 1999-2001

Research

Genetic mutations and environmental insults that disrupt the structure of the air-blood barrier can lead to death shortly after birth or life-long lung disease. The focus of Dr Weaver’s research is identification of cytoprotective pathways that mediate adaptation to genetic and environmental stresses in the pulmonary epithelium. These molecular pathways play a critical role in preventing or slowing the progression of chronic lung disease and may provide novel targets for therapeutic intervention.

Visit the Weaver Lab Site.

Research Grants and Contracts

P01HL61646 Weaver (PI) 08/10/04-06/30/09
NIH/NHLBI
Regulation of Respiratory Epithelial Cell Homeostasis
Project 1: Role of ERAD in Epithelial Cell Homeostasis (Weaver).
The goals of this project are to 1) identify the role of ERAD in SP-C induced cytotoxicity, 2) identify ERAD proteins involved in quality control of SP-C, 3) functionally characterize the quality control machinery, and 4) determine if enhanced ERAD ameliorates SP-C induced cytotoxicity intransgenic mice.
Core A: Administrative Core
Role: Program Director and Project Leader (Project 1)

R37HL56285 Weaver (PI) 05/01/06-04/30/2011
NIH/NHLBI
Structure/Function Analyses of SP-B in Transgenic Mice.
This application will test the hypotheses that 1) peptides derived from the mature SP-B peptide are potent antimicrobial regents, 2) the C-terminal peptide of proSP-B plays an important role in maintaining alveolar sterility, and 3) a saposin-like domain in the propeptide of proSP-B plays a critical role in alveolar sterility.
Role: PI

R56-AI/HL086492 Weaver (PI) 12/01/2008-11/30/2013
NIH/NHLBI/NIAID
Role of SFTPC in Pathogenesis of Interstitial Lung Disease.
This application tests the central hypothesis that environmental stress superimposed on a SFTPC mutation leads to accumulation of misfolded cytotoxic SP-C that, in turn, results in type II epithelial cell injury/death, which is the inciting event in familial ILD.
Role: PI

R01-AI/HL050797 Akinbi (PI) 08/01/2008-07/31/2009
NIH/NIAID/NHLBI
Role of Lysozyme in Airway Host Defense.
This application tests the central hypothesis that lysozyme plays a dual role in pulmonary innate immunity by directly killing bacteria and rapidly degrading proinflammatory bacterial cell wall components (peptidoglycan and its fragments).
Role: Co-PI

Publications, Most Recent

View Tim Weaver's Publications at Cincinnati Children's as listed by PubMed.

Bridges JP, Xu Y, Na CL, Wong HR, and Weaver TE. Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C.J Cell Biol 172: 395-407, 2006.

Ikegami M., Weaver T.E., Grant S.N. and Whitsett J.A. Pulmonary surfactant surface tension influences alveolar capillary shape and oxygenation. American Journal of Respiratory Cell and Molecular Biology, in press.

Ruppert C., Mahavadi P., Wygrecka M., Weaver T.E., Magdolen V., Idell S., Preissner K.T., Seeger W., Günther A. and Markart P. Recombinant production of a hybrid plasminogen activator composed of surfactant protein B and low-molecular-weight urokinase. Thrombosis and Hemostasis 100:1185-1192, 2008.

Nerelius C., Martin, E., Peng, S., Gustafsson, M., Nordling, K., Weaver, T.E. and Johansson, J. Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C.The Biochemical Journal 416:201-209, 2008.

Korfei, M., Ruppert, C., Mahavadi, P., Henneke, I., Markart, P., Koch, M., Lang, G., Fink, L., Bohle, R-M., Seeger, W., Weaver, T.E. and Guenther A. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 178:838-846, 2008.

Editorial Comment: Horowitz J.C. and Limper A.H. Stress in the ER (endoplasmic reticulum): a matter of life and death for epithelial cells. American Journal of Respiratory and Critical Care Medicine. 178:782-783, 2008.

Dong, M., Bridges, J.P., Apsley, K., Xu, Y. and Weaver, T.E. ERdj4 and ERdj5 are required for ERAD of misfolded surfactant protein C. Molecular Biology of the Cell 19:2620-2630, 2008.

Ueno, T., Elmberger, G., Weaver, T.E., Toi, M. and Linder, S. The aspartic protease napsin A suppresses tumor growth independent of its catalytic activity.Laboratory Investigation 88:256-263, 2008.

Stahlman, M.T., Besnard V., Wert, S.E., Weaver, T.E., Dingle, S., Xu, Y., von Zychlin, K., Olson, S.J. and Whitsett, J.A.: Expression of ABCA3 in developing lung and other tissues. Journal of Histochemistry and Cytochemistry 55:71-83, 2007.

Bridges, J.P. and Weaver, T.E.: Use of transgenic mice to study lung morphogenesis and function.Institute for Laboratory Animal Research 47:22-31, 2006.

Akei, H., Whitsett, J.A., Buroker, M., Ninomiya, T., Tatsumi, H., Weaver, T.E. and Ikegami, M.: Surface tension influences cell shape and phagocytosis in alveolar macrophages.American Journal of Physiology: Lung Cell and Molecular Physiology 291:L572-L579, 2006.

Johansson, H., Nordling, K., Weaver, T.E. and Johansson, J.: The brichos domain-containing C-terminal part of pro-surfactant protein C binds to an unfolded poly-Val transmembrane segment. Journal of Biological Chemistry 281:21032-21039, 2006.

Nash, J.A., Ballard, T.N.S., Weaver, T.E. and Akinbi, H.T.: The peptidoglycan-degrading property of lysozyme is not required for bactericidal activity in vivo.Journal of Immunology 177:519-526, 2006.

Bridges, J.P., Na, C-L., Wong, H.R. and Weaver, T.E.: Adaptation and incresed susceptibility to infection associated with constitutive expression of misfolded SP-C. Journal of Cell Biology 172:395-407, 2006.

Serrano, A.G., Ryan, M., Weaver, T.E. and Pérez-Gil, J.: Critical structure-function determinants within the N-terminal region of Pulmonary Surfactant Protein SP-B.Biophysical Journal 90:238-249, 2006.

Ikegami, M., Whitsett, J.A., Martis, P.C. and Weaver, T.E.: Reversibility of lung inflammation caused by SP B deficiency. American Journal of Physiology: Lung Cell and Molecular Physiology 289:L962-L970, 2005.

Ryan, M.A., Akinbi, H.T., Serrano, A.G., Perez-Gil, J., Wu, H., McCormack, F.X. and Weaver, T.E.: Antimicrobial activity of native and synthetic surfactant protein B peptides. Journal of Immunology 176:416-425, 2006.

Nesslein, L.L., Melton, K.R., Ikegami, M., Na, C-L., Wert, S.E., Rice, W.R., Whitsett, J.A. and Weaver, T.E.: Partial SP-B deficiency perturbs lung function and causes air space abnormalities.American Journal of Physiology: Lung Cell and Molecular Physiology 288:1154-1161, 2005.

Ryan, M.A., Qi, X., Serrano, A.G., Ikegami, M., Perez-Gil, J., Johansson, J. and Weaver, T.E.: Mapping and analysis of the lytic and fusogenic domains of surfactant protein B. Biochemistry 44:861-872, 2005.

Li, J., Hosia, W., Hamvas, A., Thyberg, J., Jörnvall, H., Weaver, T.E. and Johansson, J.: The N-terminal propeptide of lung surfactant protein C is necessary for biosynthesis and prevents unfolding of a metastable a-helix.Journal of Molecular Biology 338:857-862, 2004.

Markart, P., Faust, N., Graf, T., Na, C.-L., Weaver, T.E. and Akinbi, H.T.: Comparison of the microbicidal and muramidase activities of mouse lysozyme M and P. Biochemical Journal 380:385-392, 2004.

Bridges, J.P., Wert, S.E., Nogee, L.M. and Weaver, T.E.: Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice. Journal of Biological Chemistry 278:52739-52746, 2003.

deFelice, M., Silberschmidt, D., DiLauro, R., Xu, Y., Wert, S.E., Weaver, T.E., Bachurski, C.J., Clark, J.C. and Whitsett, J.A.: TTF-1 phosphorylation is required for peripheral lung morphogenesis, perinatal survival, and tissue specific gene expression.Journal of Biological Chemistry 278:35574-35583, 2003.

Johansson, J., Weaver, T.E. and Tjernberg, L.O.: Proteolytic generation and aggregation of peptides from transmembrane regions. Lung surfactant protein C and amyloid ß-peptide. Cellular and Molecular Life Sciences 61:326-335, 2004.

Melton, K.R., Nesslein, L.L., Ikegami, M., Tichelaar, J.W., Clark, J.C., Whitsett, J.A. and Weaver, T.E.: SP B deficiency causes respi¬ra¬tory failure in adult mice.American Journal of Physiology: Lung, Cellular and Molecular Physiology 285:L543-L549, 2003

Epaud, R., Ikegami, M., Whitsett, J.A., Jobe, A.H., Weaver, T.E. and Akinbi, H.T.: Surfactant protein B inhibits endotoxin-induced lung inflammation.American Journal of Respiratory Cell and Molecular Biology 28:373-378, 2003.

Ikegami, M., Takabatake, N. and Weaver, T.E.: The intersubunit disulfide bridge is not required for the protective role of SP-B against lung inflammation. Journal of Applied Physiology 93:505-511, 2002.

Whitsett, J.A. and Weaver, T.E.: Hydrophobic surfactant proteins in lung function and disease.New England Journal of Medicine 347:2141-2148, 2002.

Rice, W.R., Conkright, J.J., Na, C-L., Ikegami, M., Shannon, J. and Weaver, T.E.: Maintenance of the mouse Type II cell phenotype in vitro.American Journal of Physiology 283:L256-L264, 2002.

Weaver, T.E., Na, C.-L.. and Stahlman, M.: Biogenesis of lamallar bodies, lysosome related organelles specialized for storage and secretion of pulmonary surfactant.Seminars in Cell and Developmental Biology 13:263-270, 2002.

Conkright, J.J., Na, C.-L. and Weaver, T.E.: Overexpression of SP-C mature SP-C peptide causes neonatal lethality in transgenic mice.American Journal of Respiratory Cell and Molecular Biology 26:85-90, 2002.

Ikegami, M., Weaver, T.E., Conkright, J.J., Sly, P.D., Ross, G.F., Whitsett, J.A. and Glasser, S.W.: Deficiency of SP-B reveals protective role of SP-C during oxygen injury. Journal of Applied Physiology 92:519-526, 2002.

Zaltash, S., Griffiths, W.J., Beck, D., Duan, C-X., Weaver, T.E. and Johansson, J.: Membrane activity of (Cys48Ser) lung surfactant protein B increases with dimerisation. Biological Chemistry 382:933-939, 2001.

Conkright, J.J., Bridges, J.P., Na, C.-L., Voorhout, W.F., Trapnell, B., Glasser, S.W. and Weaver, T.E.: Secretion of surfactant protein C, an integral membrane protein, requires the N-terminal propeptide.Journal of Biological Chemistry 276:14658-14664, 2001.

Mishra, A., Weaver, T.E., Beck, D.C. and Rothenberg, M.E.: IL-5 mediated allergic airway inflammation inhibits the human surfactant protein C promoter in transgenic mice. Journal of Biological Chemistry 276:8453-8459, 2001.

Ueno, T, Linder, S, Na, C-L, Rice, WR, Johansson, J and Weaver, TE: Processing of pulmonary surfactant protein B by napsin and cathepsin H. Journal of Biological Chemistry 279:16178-16184, 2004.

Li, J, Ikegami, M, Na, C-L, Hamvas, A, Espinassous, Q, Chaby, R, Nogee, LM, Weaver, TE and Johansson, J: N-terminally extended surfactant protein (SP) C isolated from SP-B-deficient children has reduced surface activity and inhibited lipopolysaccharide binding. Biochemistry 43:3891-3898, 2004.

Markart, P, Korfhagen, TR, Weaver, TE and Akinbi, HT: Mouse lysozyme M is important in pulmonary host defense against Klebsiella pneumoniae infection.American Journal of Respiratory and Critical Care Medicine 169:454-458, 2004.

Professional Organization Memberships

  • American Lung Association National Fellowship Review Committee, 1996-1999
  • Gene Therapy Centers Review, NIDDK, 1998
  • Physiology Special Emphasis Panel (NIH Study Section), 1997
  • Respiratory & Applied Physiology Study Section (ad hoc), 1994
  • External Advisory Board, Institute for Environmental Medicine, 1994-2004
  • Editorial Board, American Journal of Physiology: Lung Cellular and Molecular Physiology, 1994-1999
  • Editorial Board, Cellular and Molecular Life Sciences, 2004-2007

Special Interests

Initiation of air breathing at birth is dependent upon an highly orchestrated developmental program leading to the formation of an extensive gas exchange surface (air-blood barrier). Genetic mutations and environmental insults that disrupt the structure of the air-blood barrier can lead to death shortly after birth or life-long lung disease. Cytoprotective pathways involved in adaptation to genetic and environmental stresses play a critical role in preventing or slowing the progression of chronic lung disease and may provide novel targets for therapeutic intervention. Dr. Weaver's lab is currently studying two important pathways involved in protection of the epithelial surface of the air-blood barrier:

  • ERAD involves the selective recognition and rapid elimination of misfolded proteins (arising from inherited or spontaneous mutations) to prevent epithelial cell injury and death.
  • Antimicrobial peptides recognize and promote clearance of inhaled microorganisms to prevent colonization of the airspaces and injury to epithelial cells.

Faculty