The glycosyl hydrolase 18 (GH18) gene family contains evolutionarily conserved chitinase-like proteins (CLP) that are presumed to play essential roles in biology. However, their functional profiles have just begun to be investigated. We recently demonstrated that the prototypic CLP (YKL-40 in man and BRP-39 in the mouse) is a circulating regulator of apoptosis, alternative (M2) macrophage activation and TGF-bi elaboration and tissue fibrosis. We also identified the first receptor for any GH18 moiety, IL-13 receptor(R)a2. Studies of patients with idiopathic pulmonary fibrosis (IPF) revealed elevated levels of plasma YKL-40 that correlated with adverse outcomes. After kidney transplant, urinary YKL-40 levels were increased in patients with delayed graft function (DGF). These findings led us to hypothesize that (a) elevated levels of YKL-40 are biomarkers of risk-stratification in IPF and DGF;(b) YKL-40 is produced by epithelial cells and macrophages and mediates its effects by stimulating TGF-b1 and M2 macrophage activation via IL-13Ra2;(c) YKL-40 and IL-13Ra2 are therapeutic targets in IPF and DGF. To test this hypothesis we will evaluate YKL-40 as a biomarker in two separate cohorts of patients, one with IPF and one with DGF. We will also evaluate the mechanisms it uses to mediate its cellular effects and the utility of YKL-40/BRP-39 and IL-13Ra2 as therapeutic targets in these disorders. We will;
Aim 1. Define the levels of circulating YKL-40 and their roles as biomarkers in IPF.
Aim 2. Define the levels of circulating &urinary YKL-40 and their roles as biomarkers in DGF.
Aim 3. Characterize the location and molecular profile of YKL-40 in IPF and DGF.
Aim 4. Characterize the relationships between YKL-40, IL-13Ra2 and TGF-|31 and the ability of YKL-40 to regulate monocyte lineage cell fate and accumulation in IPF and DGF.
Aim 5. Characterize the roles of BRP-39 and IL-13Ra2 in murine lung fibrosis and ischemia/reperfusion kidney injury models.

Public Health Relevance

We have identified a relationship between the chitinase-like protein YKL-40 and two different forms of maladaptive repair in humans. Idiopathic Pulmonary Fibrosis and Delayed Graft Function following renal transplantation. In this grant we will explore the utility of YKL-40 to serve as a predictor of progression in these diseases, define the mechanism through which YKL-40 exerts its effects on fibrosis, and determine whether this pathway is a therapeutic target in one or both of these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL108638-02
Application #
8320196
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Eu, Jerry Pc
Project Start
2011-08-15
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$658,115
Indirect Cost
$261,660
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
Tran, Hoa T; Lee, In-Ah; Low, Daren et al. (2014) Chitinase 3-like 1 synergistically activates IL6-mediated STAT3 phosphorylation in intestinal epithelial cells in murine models of infectious colitis. Inflamm Bowel Dis 20:835-46
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