Chitin and chitin synthase do not exist in man. However, chitinases and chitinase-like proteins (C/CLP) have recently been appreciated. This includes true chitinases and moieties that lack chitinase activity like breast regression protein-39 (BRP-39) and its human homologue YKL-40. BRP-39 and YKL-40 are expressed in an exaggerated fashion in a variety of diseases. However, virtually nothing is known about their roles in mammalian or human biology. We studied the regulation and roles of BRP-39 in allergic inflammation. These studies demonstrate that (a) BRP-39 is prominently induced at sites of Th2 and IL-13-induced inflammation, (b) BRP-39-/- mice have a significant defect in Th2 and IL-13-induced inflammation and remodeling that is associated with enhanced T cell and macrophage apoptosis and Fas expression and (c) BRP-39/YKL-40-induced cytoprotection is associated with enhanced protein kinase B/Akt activation. They also demonstrate that BRP-39/YKL-40 binds to IL-13 receptor (R)a2 and activates mitogen activated protein kinases (MAPK) and PKB/Akt via an IL-13Ra2- dependent mechanism. Lastly, they highlight the human relevance of these findings by demonstrating that YKL-40 is found in exaggerated quantities in the serum and lungs from severe asthmatics and that chitinase 3- like 1 is an asthma susceptibility gene. This led us to the following hypothesis. HYPOTHESIS: 1. BRP-39/YKL-40 is induced during and plays a critical and selective role in the pathogenesis of adaptive Th2 inflammation and remodeling. 2. BRP-39 and YKL-40 are important regulators of T cell and macrophage apoptosis/cell death. 3. BRP-39 and YKL-40 mediate their tissue responses via a pathway(s) that involves IL-13Ra2, MAPK and or PKB/Akt. To test this hypothesis we propose to:
AIM 1. Characterize the expression and roles of BRP-39 in Th2 and Th1 inflammation and remodeling.
AIM 2. Characterize the relative contributions of serum and tissue and epithelial- and macrophage-derived BRP-39/YKL-40 in Th2 and IL-13-induced inflammation and remodeling.
AIM 3. Define the interactions of BRP-39/YKL-40 and IL-13Ra2 and the roles of IL-13Ra2 in the pathogenesis of the biologic effects of BRP-39/YKL-40.
AIM 4. Characterize the mechanisms of the exaggerated T cell and macrophage apoptosis/cell death responses in BRP-39-/- mice and the relevance of this cell death pathway to humans.

Public Health Relevance

Our studies demonstrated that a protein named BRP-39 plays a critical role in asthma-like inflammation in the mouse and that the human equivalent, YKL-40, is found in exaggerated quantities in the circulation of people with severe asthma. They also demonstrated that BRP-39/YKL-40 likely mediates its biologic effects by controlling the death of inflammatory cells. This proposal will investigate the processes that regulate the production of this molecule and define the receptor, signaling pathways and mechanisms that it uses to regulate cell death.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093017-04
Application #
8402992
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2010-01-18
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$389,951
Indirect Cost
$154,331
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Jafari, Behrouz; Elias, Jack A; Mohsenin, Vahid (2014) Increased plasma YKL-40/chitinase-3-like-protein-1 is associated with endothelial dysfunction in obstructive sleep apnea. PLoS One 9:e98629
Zhou, Yang; Peng, Hong; Sun, Huanxing et al. (2014) Chitinase 3-like 1 suppresses injury and promotes fibroproliferative responses in Mammalian lung fibrosis. Sci Transl Med 6:240ra76
Hall, Isaac E; Stern, Edward P; Cantley, Lloyd G et al. (2014) Urine YKL-40 is associated with progressive acute kidney injury or death in hospitalized patients. BMC Nephrol 15:133
Gavala, M L; Kelly, E A B; Esnault, S et al. (2013) Segmental allergen challenge enhances chitinase activity and levels of CCL18 in mild atopic asthma. Clin Exp Allergy 43:187-97

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