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.
Our studies demonstrated that a protein named BRP-39 plays a critical role in asthma-like inflammation in themouse and that the human equivalent; YKL-40; is found in exaggerated quantities in the circulation of peoplewith severe asthma. They also demonstrated that BRP-39/YKL-40 likely mediates its biologic effects bycontrolling the death of inflammatory cells. This proposal will investigate the processes that regulate theproduction of this molecule and define the receptor; signaling pathways and mechanisms that It uses toregulate cell death.
|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|
|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|
|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|
|He, Chuan Hua; Lee, Chun Geun; Dela Cruz, Charles S et al. (2013) Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor *2. Cell Rep 4:830-41|
|Schmidt, Insa M; Hall, Isaac E; Kale, Sujata et al. (2013) Chitinase-like protein Brp-39/YKL-40 modulates the renal response to ischemic injury and predicts delayed allograft function. J Am Soc Nephrol 24:309-19|
|Lee, Chun Geun; Dela Cruz, Charles S; Ma, Bing et al. (2012) Chitinase-like proteins in lung injury, repair, and metastasis. Proc Am Thorac Soc 9:57-61|
|Sohn, Myung Hyun; Kang, Min-Jong; Matsuura, Hiroshi et al. (2010) The chitinase-like proteins breast regression protein-39 and YKL-40 regulate hyperoxia-induced acute lung injury. Am J Respir Crit Care Med 182:918-28|