The Role Of Lysophosphatidic Acid (LPA) And Its Receptor, LPA1 In Scleroderma

描述（由申请人提供）：Castelino博士的长期目标是成为一名独立资助的研究者，在硬皮病纤维化机制方面具有专业知识。她的研究目的是研究脂质介质溶血磷脂酸（LPA）及其受体LPA1在硬皮病（SSc）真皮纤维化中的作用。Castelino博士建议研究LPA-LPA1通路调节皮肤纤维化的机制，并确定这种新通路与TGF-¿的相互作用，TGF-¿是SSc发病机制的中心介质。她的近期目标是学习(1)分子生物学的新技术，包括条件基因靶向；(2) TGF-通路成分（包括v-整合素）的体内和体外实验；(3)进行转化研究的技能。作为一名大三学生

DESCRIPTION (provided by applicant): Dr. Castelino's long-term goal is to become an independently funded investigator with an expertise in mechanisms of fibrosis in scleroderma. The goal of her research is to study the roles of the lipid mediator lysophosphatidic acid (LPA) and its receptor LPA1 in scleroderma (SSc) dermal fibrosis. Dr. Castelino proposes to investigate the mechanisms by which the LPA-LPA1 pathway regulates dermal fibrosis, and determine the interplay of this novel pathway with TGF-¿, a central mediator in the pathogenesis of SSc. Her immediate objectives are to learn (1) new techniques in molecular biology including conditional gene targeting; (2) in vivo and in vitro experimentation with components of the TGF-¿ pathway including ¿v-integrins; and (3) skills for conducting translational research. As a junior faculty member at Massachusetts General Hospital (MGH), Dr. Castelino will benefit from interactions with basic scientists and clinical researchers. She will enhance her training through didactic seminars offered through MGH and the Harvard Clinical and Translational Science Center, and formal coursework at Harvard Medical School. Dr. Castelino will benefit from the mentorship of Drs. Andrew Tager and Robert Lafyatis and members of her advisory committee who have expertise in studying the pathogenesis of fibrosis, ¿v-integrin biology and TGF-¿ signaling, and translational research. In the first part of her proposal she will evaluate the roleof LPA-LPA1 signaling in myofibroblast accumulation in dermal fibrosis using transgenic mice to investigate fibroblasts specifically, and she will perform in vitro studies to evaluate fibroblast proliferation and apoptosis. In the second part of her proposal, she will investigate the role of LPA-LPA1 in TGF-¿ activation, and assess whether ¿v integrins are a key mediator of this process, by manipulating gene expression of the ¿v-integrin subunit in vivo. In the final part of her proposal, she will evaluate the role of LPA-LPA1 signaling in SSc patients using peripheral blood and skin biopsy samples. Together these studies will characterize the mechanisms by which LPA and LPA1 mediate myofibroblast accumulation and TGF-¿ signaling. These studies will serve as a foundation for Dr. Castelino to become an independent translational investigator.