Chitinase1 as a Biomarker and Therapeutic Target in Scleroderma Lung Disease

描述（由申请人提供）：Chitotriosidase （chitinase 1; Chit1）是人类主要的真正几丁质酶，是糖基水解酶18 （GH18）基因家族的成员。它可以在正常人的血液循环中发现可检测到的量，并且在以炎症、组织重塑和/或纤维化为特征的各种疾病中进一步增加，包括细菌或真菌感染、溶酶体贮积病（戈谢氏病）、结节病和间质性肺疾病。然而，Chit1的效应函数尚未定义，且其

DESCRIPTION (provided by applicant): Chitotriosidase (chitinase 1; Chit1), a member of the glycosyl hydrolase 18 (GH18) gene family, is the major true chitinase in humans. It can be found in detectable quantities in the circulation of normal individuals and is further increased in a variety of diseases characterized by inflammation, tissue remodeling and/or fibrosis including bacterial or fungal infections, lysosomal storage diseases (Gaucher's), sarcoidosis, and interstitial lung diseases. However, the effector functions of Chit1 have not been defined, and its roles in the pathogenesis of these diseases have not been elucidated. To begin to define the in vivo roles of Chit1 in pulmonary injury and repair, we characterized the levels of circulating Chit activity in patients with Scleroderma (SSc) and have begun to investigate the bleomycin-induced responses in newly generated Chit1 null mutant mice (Chit1-/-), lung-targeted Chit1 overexpressing transgenic mice (Chit1 Tg), and humanized Chit1 bacterial artificial chromosome (BAC) mice (HBAC-Chit) that contain human Chit1 and its regulatory sequences on a murine Chit1-/- background. Using yeast two hybrid assays, we have also identified potential partners/receptors that Chit1 binds to. These studies demonstrate that (a) the levels of circulating Chit1 activity are increased in patients with SSc where they correlate with the presence and severity of interstitial lung disease (SSc-ILD); (b) Chit1 is induced in macrophages and alveolar type II cells after bleomycin challenge; and (c) bleomycin-induced fibrosis is significantly ameliorated in Chit1-/- mice, but enhanced in Chit1 Tg mice compared to wild type (WT) controls. They also demonstrate that Chit1 augments TGF-�1-induced fibroblast proliferation, receptor expression and canonical and non-canonical signaling while binding to TGF-� receptor associated protein-1 (Tgfbrap1). These findings led us to hypothesize that Chit1 is a biomarker of and also a therapeutic target in SSc-ILD patients. These studies also suggest that Chit1 mediates its fibrotic effects, at least in part, via its ability to augment TGF-�1 responses by interacting with Tgfbrap1. To test the hypotheses, the studies in this project will use in vivo and in vitro and translational approaches to: 1. Define the levels of circulating Chit1 and Chit1 bioactivity and their roles as biomarkers in SSc. 2. Define the roles of Chit1 in the pathogenesis of bleomycin- and IL-13-induced fibrosis. 3. Define the mechanisms that Chit1 uses to augment tissue fibrosis. 4. Define the interaction of Chit1 with Tgfbrap1 and the role(s) of this interaction in the pathogenesis of the biologic effects of Chit1.