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

描述(申请人提供)：卡斯特利诺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体溶血磷脂酸(LPA)及其受体LPA1在硬皮病(SSC)皮肤纤维化中的作用。Castelino博士建议研究LPA-LPA1途径调节皮肤纤维化的机制，并确定这一新途径与转化生长因子-β的相互作用，转化生长因子-β是SSC发病机制中的中心介质。她目前的目标是学习(1)分子生物学的新技术，包括条件基因打靶；(2)体内和体外对转化生长因子途径的组件进行实验，包括v-整合素；以及(3)进行翻译研究的技能。作为一个大三学生 作为马萨诸塞州总医院(MGH)的一名教员，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和哈佛临床与转化科学中心提供的授课研讨会以及哈佛医学院的正式课程来加强她的培训。卡斯特利诺博士将受益于安德鲁·泰格博士和罗伯特·拉菲蒂斯博士以及她的顾问委员会成员的指导，他们在研究纤维化的发病机制、v-整合素生物学和转化生长因子信号以及翻译研究方面拥有专业知识。在她的提案的第一部分，她将使用转基因小鼠来专门研究成纤维细胞，评估LPA-LPA1信号在真皮纤维化中肌成纤维细胞聚集中的作用，并将进行体外研究，以评估成纤维细胞的增殖和凋亡。在她的提案的第二部分，她将研究LPA-LPA1在转化生长因子-β激活中的作用，并通过操纵体内整合素亚单位的基因表达来评估整合素是否是这一过程的关键中介。在她的提案的最后部分，她将使用外周血和皮肤活检样本来评估LPA-LPA1信号在SSC患者中的作用。这些研究将共同描述LPA和LPA1介导肌成纤维细胞聚集和转化生长因子-β信号转导的机制。这些研究将为卡斯特利诺博士成为一名独立的翻译研究员奠定基础。 与公共卫生相关：硬皮病是一种自身免疫性疾病，影响多个器官，导致皮肤和内部器官纤维化或硬化。这种疾病与高死亡率有关，到目前为止还没有有效的治疗方法。对导致硬皮病纤维化的介质的更好的理解有望导致更好的治疗选择。

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. PUBLIC HEALTH RELEVANCE: Scleroderma is an autoimmune disease that affects multiple organs and causes fibrosis or hardening of the skin and internal organs. This disease is associated with high mortality, and to date there is no effective therapy. An improved understanding of the mediators that drive scleroderma fibrosis will hopefully result in better treatment options.