Division of Intramural Research
Pulmonary Critical Care Medicine Branch

Joel Moss
M.D., Ph.D., New York University School of Medicine, 1972

National Institutes of Health
10 Center Drive, Building 10 / Room 6D05
Bethesda, Maryland 20892-1590
Phone Number: 301-496-1597
Fax Number: 301-496-2363
Email Address: mossj@nhlbi.nih.gov

Research Interest(s):

Pulmonary / Respiratory Diseases
Molecular & Cellular Biology
Genetics and Human Genome

Research Description:

Signal Transduction in Health and Disease

Our laboratory has ongoing basic and clinical research programs to investigate signal transduction pathways in health and disease. Basic research focuses on guanine nucleotide-binding proteins and post-translational modification of proteins. The activity of signal transduction pathways involving guanine nucleotide-binding proteins is determined, in part, by the incorporation of critical proteins and their interacting partners into soluble and/or membrane-associated macromolecular complexes, linked to upstream and downstream regulatory molecules. The compositions of these complexes are being defined through genomic and proteomic techniques. Within these complexes, the activities of individual proteins are modulated by post-translational modification, a dynamic process that permits rapid changes in activity in response to exogenous or endogenous stimuli. ADP-ribosylation, in which the common metabolite NAD is the donor of ADP-ribose for modification of proteins, is used by bacterial toxins to disrupt mammalian metabolic and signaling pathways (e.g., Pseudomonas aeruginosa cytotoxins). In mammalian cells, intracellular ADP-ribosylation appears to be a reversible process, with an ADP-ribosylarginine hydrolase responsible for removal of ADP-ribose from proteins and regeneration of the unmodified proteins. Extracellular ADP-ribosylation participates in the regulation of basic proteins involved in the innate immune response. ADP-ribosylation of defensin, a cytotoxic host-defense molecule, alters its function selectively, downregulating its cytotoxic activity without altering its chemotactic properties.

Areas of clinical and translational research include lymphangioleimyomatosis (LAM) and other destructive lung diseases (e.g., cystic fibrosis), with primary emphasis on the roles of susceptibility/modifier genes and infection/inflammation on disease progression and severity. In LAM, a disease primarily of middle-aged women, lung destruction is mediated by abnormal, immature-appearing smooth muscle cells that express genes usually found in melanocytes and melanomas. The prevalence of LAM is increased among individuals with mutations in the tuberous sclerosis (tsc) genes, which encode proteins that may function as tumor suppressors and regulate the activity of guanine nucleotide-binding proteins involved in vesicular trafficking. Cultured LAM cells grown from lung explants have mutations in their tsc genes and exhibit properties of both smooth muscle and melanoma cells. In LAM and other destructive lung diseases under study, genetic factors have been identified that influence disease progression through effects on inflammation, the pulmonary circulation (e.g., blood flow and recruitment of inflammatory cells in alpha1-antitrypsin deficiency), or susceptibility to infection (e.g., Pseudomonas aeruginosa infection in cystic fibrosis).

Selected Publications:

Cellular Heterogeneity in Lymphangioleiomyomatosis (LAM). JA Kelly, SC Chu, J Moss. In J. Moss (ed.): Marcel Dekker, Inc. Publishers. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY. :501-516(1998). 

Molecules in the ARF Orbit. J Moss, M Vaughan. Journal of Biological Chemistry 273:21431-21434(1998). PubMed

Glycosylphosphatidylinositol-anchored and Secretory Isoforms of Mono-ADP-ribosyltransferases. IJ Okazaki, J Moss. Journal of Biological Chemistry 273:23617-23620(1998). PubMed

Endothelial Nitric Oxide Synthase as a Potential Susceptibility Gene in the Pathogenesis of Emphysema in a1-Antitrypsin Deficiency. A Novoradovsky, ML Brantly, MA Waclawiw, PP Chaudhary, H Ihara, L Qi, N Eissa, PM Barnes, KM Gabriele, ME Ehrmantraut, P Rogliani, J Moss. Am. J. Respir. Cell Mol. Biol. 20:442-447(1999). 

Meningiomas in Lymphangioleiomyomatosis (LAM). J Moss, R DeCastro, NJ Patronas, A Taveira-DaSilva. Journal of the American Medical Association 286:1879-81(2001). 

Last updated August 29, 2002

Principal Investigators

• Joel Moss
• Martha Vaughan
• Vincent Manganiello
• Bernadette Gochuico
• Stewart Levine