Neutral metalloendopeptidase 3.4.24.11 (Neprilysin, NEP) is a protease located on the surface of a wide variety of cells in the nervous system in a localization which suggests a modulatory role in the metabolism of endogenous opiate compounds. Within the lung, the enzyme may suppress neurogenic inflammation induced by tachykinins and potentially regulates endogenous growth factors such as bombesin-like peptides. Renal expression of NEP appears to abrogate the activities of a variety of cardiovascular regulatory peptides such as atrial naturetic factor and endothelin. In the immune system, the enzyme is expressed on pro B cells and neutrophils, where it was characterized as the common acute lymphoblastic leukemia antigen, CALLA. The objective of this research program is to explore the central hypothesis that NEP serves as a biological control mechanism to modulate the actions of diverse biologically active peptides in the brain, lung and immune system. Secondary hypotheses are that alternative processing of the NEP gene leads to a biologically novel enzyme MME II and that the enzyme itself is subject to regulation .
Five specific aims are proposed to test these hypotheses.
Aims 1 -3 will characterize the phenotype of mice engineered genetically deficient in NEP expression. We will focus on three well characterized models (analgesia/enkephalinase; tachykinin-induced inflammation and bronchoconstriction/NEP; and ontogeny of the lymphoid compartment/CALLA) where inhibitor studies have suggested a possible key role for the enzyme as a biological modulator.
Aim 4 will construct and characterize a cDNA for MME Il, measure the tissue distribution of the transcript quantitatively, and characterize the protein in vitro and potentially in vivo.
Aim 5 examines the possibility for protein downregulation through phosphorylation/internalization. The successful completion of these aims should clarify the role of the enzyme as a critical modulator of diverse processes mediated by neuropeptides and other biologically active peptides, and provide new insights into how the organism has adapted this protease to biological control. The potential for therapeutic intervention at the NEP system in opiate/alcohol dependance, pain control, heart failure and neurogenic inflammation of the lung will be advanced by these studies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052503-05
Application #
2750418
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1994-08-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
2000-07-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Gerard, C; Frossard, J L; Bhatia, M et al. (1997) Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. J Clin Invest 100:2022-7