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人员，在硬皮病纤维化机制方面具有专业知识。她的研究目标是研究脂质介质溶血磷脂酸（LPA）及其受体LPA 1在硬皮病（SSc）皮肤纤维化中的作用。Castelino博士建议研究LPA-LPA 1途径调节真皮纤维化的机制，并确定这种新途径与TGF-β的相互作用，TGF-β是SSc发病机制中的中心介质。她的近期目标是学习（1）分子生物学新技术，包括条件基因靶向;（2）体内和体外实验与TGF-β途径的组成部分，包括β v-整合素;和（3）进行翻译研究的技能。作为一个初级 作为马萨诸塞州总医院（MGH）的教员，Castelino博士将从与基础科学家和临床研究人员的互动中受益。她将通过MGH和哈佛临床和转化科学中心提供的教学研讨会以及哈佛医学院的正式课程来加强她的培训。Castelino博士将受益于Andrew Tager博士和Robert Lafyatis博士以及她的咨询委员会成员的指导，他们在研究纤维化的发病机制，β-整合素生物学和TGF-β信号传导以及转化研究方面具有专业知识。在她的提案的第一部分，她将评估LPA-LPA 1信号在皮肤纤维化中肌成纤维细胞积累中的作用，使用转基因小鼠专门研究成纤维细胞，她将进行体外研究以评估成纤维细胞增殖和凋亡。在她的提案的第二部分，她将研究LPA-LPA 1在TGF-β激活中的作用，并通过操纵体内β-整联蛋白亚基的基因表达来评估β-整联蛋白是否是这一过程的关键介质。在她的提案的最后一部分，她将使用外周血和皮肤活检样本评估LPA-LPA 1信号在SSc患者中的作用。这些研究将共同表征LPA和LPA 1介导肌成纤维细胞积累和TGF-β信号传导的机制。这些研究将为Castelino博士成为独立的翻译研究者奠定基础。

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.