Thomas L. Leto, Ph.D.

Senior Investigator

This section is studying signaling pathways that link receptor activation in phagocytes to the release of reactive oxygen species, which serve in host defense and promotion of inflammatory responses (current emphasis on phospholipases). Other work is characterizing a family of oxidases related to the phagocyte system that serve a variety of tissue-specific functions (oxygen sensing, host defense, proliferation, differentiation, and cellular senescence).

Description of Research Program

This group studies structure-function relationships in the NADPH oxidase of phagocytic blood cells, including structural mutations detected in chronic granulomatous disease; characterization of regulatory proteins that affect NADPH oxidase function (Ras-related proteins, Src homology domains, phospholipases, and protein kinases); and signal transduction processes involved in neutrophil activation.

Renox expression in mouse kidney.

Recent accomplishments include the demonstration that assembly of activated NADPH oxidase involves interactions of Src homology 3 domains with proline-rich targets in other oxidase components, and that other proline-rich or SH3 domain-containing proteins can downregulate the oxidase. Phospholipases A2 and D were also implicated in phagocyte activation in transfected cell models. These observations may serve as a basis for drugs designed to limit or augment oxidant production at sites of inflammation or infection.

Future directions include defining regulatory mechanisms in receptor-mediated NADPH oxidase activation and establishing their relevance to other intracellular signal transduction pathways. We are also studying sources of reactive oxidants in a variety of other tissues and exploring their roles in health and disease.

Research Group Members

Miklos Geiszt, Raya Dana, Cedric Dewas, Kristen Lekstrom.

Selected Recent Publications

To view a complete listing, visit PubMed.

Lavigne MC, Malech HL, Holland SM, Leto TL. Genetic demonstration of p47phox-dependent superoxide anion production in murine vascular smooth muscle cells. Circulation. 2001. 104: 79-84.

Lavigne MC, Malech HL, Holland SM, Leto TL. Genetic requirement of p47phox for superoxide production by murine microglia. FASEB J. 2001. 15: 285-287.

Dana RR, Eigsti C, Holmes KL, Leto TL. A regulatory role for ADP-ribosylation factor 6 (ARF6) in activation of the phagocyte NADPH oxidase. Biol Chem. 2000. 275: 32566-32571.

Geiszt M, Kopp JB, Varnai P, Leto TL. Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A. 2000. 97: 8010-8014.

Huang CK, Zhan L, Hannigan MO, Ai Y, Leto TL. P47(phox)-deficient NADPH oxidase defect in neutrophils of diabetic mouse strains, C57BL/6J-m db/db and db/+. J Leukoc Biol. 2000. 67: 210-215.

Leto, TL. The respiratory burst oxidase. In: Gallin JI, Snyderman R, eds. Inflammation: Basic Principles and Clinical Correlates. Philadelphia: Lippincott-Williams and Wilkins; 1999: 769-786.

Special Interest Groups: Cell Biology, Structural Biology

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