Lysophosphatidic acid (LPA) is a novel FGF23 regulator in acute kidney injury.

项目总结/摘要 成纤维细胞生长因子-23（FGF 23）是一种骨源性激素，通过调节血磷水平来控制血磷水平。 增加肾磷酸盐排泄并减少1，25-二羟维生素D3的产生。fgf 23水平 随着肾脏疾病的增加而增加，是不良肾脏结局的一个强独立风险因素， mortality.然而，缺乏对FGF 23产生的调控机制的基本了解。 我们对FGF 23合成的肾脏介质进行了代谢组学/蛋白质组学筛选， 确定了一种新的信号传导轴，由此肾脏来源的甘油-3-磷酸（G-3-P）被转化为 溶血磷脂酸（LPA）在骨骼中，然后刺激FGF 23的合成。这份提案的重点在于此 LPA的新作用，中心假设LPA通过LPA受体1介导信号传导 在急性肾损伤（阿基）中，LPAR 1对于FGF 23的产生至关重要。在强大的初步数据支持下，我们 将使用Lpar 1敲除小鼠来剖析响应于外源LPA施用（Aim 1)和实验性阿基（Aim 2）。总之，这些研究试图建立LPA和LPAR 1作为潜在的 FGF 23介导的肾脏疾病发病率和死亡率的治疗靶点，并作为一种新的治疗方法， 在肾脏学和代谢的交叉点上独立科学生涯的跳板。 候选人Simic博士致力于肾脏病学基础研究的职业生涯。她之前 追求衰老和骨生物学的研究培训，但自从2018年完成肾脏学奖学金以来， 她将注意力转移到一个新的领域-肾脏疾病、代谢和FGF 23稳态。西米奇医生马上 职业目标包括获得本拨款申请中描述的技能和出版第一作者手稿 以获得知名度并在学术肾病学领域站稳脚跟。西米奇博士的长期职业目标是 成为一名独立的医生科学家和肾骨相互作用和矿物质的领先专家 新陈代谢.她将受益于尤金李（主要导师;首席，MGH 成人肾脏病学），肾脏代谢专家，和Harald Jueppner（共同导师，MGH儿科主任 肾脏学），矿物生物学的领导者。西米奇博士的职业发展计划将利用培训 MGH肾脏科和内分泌科以及哈佛医学院的科学资源 学校西米奇博士、李博士和朱普纳博士将经常会面，讨论科学和职业发展， 并已清楚地确定了所提出的研究的各个方面，这些方面将构成她独立职业生涯的基础。 已经成立了一个咨询委员会来评估进展情况，提供额外的指导，并规划未来的发展。 方向Simic博士将定期在MGH肾脏科和内分泌科展示她的数据 并将得到支持，在国家会议上介绍其工作。正式的课程计划在赠款写作， 公开演讲，负责任地进行研究，生物信息学，代谢组学和药物开发， 进一步提高她作为独立医生/科学家成功的可能性。

PROJECT SUMMARY/ABSTRACT Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 production. FGF23 levels increase with kidney disease and are a strong independent risk factor for adverse renal outcomes and mortality. However, fundamental understanding of what regulates FGF23 production is lacking. We performed a metabolomic/proteomic screen for renal mediators of FGF23 synthesis and have identified a novel signaling axis whereby kidney derived glycerol-3-phosphate (G-3-P) is converted to lysophosphatidic acid (LPA) in bone, which then stimulates FGF23 synthesis. This proposal focuses on this novel role for LPA, with the central hypothesis that LPA mediated signaling through the LPA receptor 1 (LPAR1) is critical for FGF23 production in acute kidney injury (AKI). Supported by strong preliminary data, we will use Lpar1 knockout mice to dissect this pathway in response to both exogenous LPA administration (Aim 1) and in experimental AKI (Aim 2). Together, these studies seek to establish LPA and LPAR1 as potential therapeutic targets for FGF23 mediated morbidity and mortality in kidney disease, and to serve as a springboard for an independent scientific career at the intersection of nephrology and metabolism. The candidate, Dr. Simic, is dedicated to a career in basic investigation in nephrology. She previously pursued research training in aging and bone biology, but since completing nephrology fellowship in 2018, has shifted her focus to a new area—kidney disease, metabolism, and FGF23 homeostasis. Dr. Simic’s immediate career goals include acquiring the skills described in this grant proposal and publishing first author manuscripts to gain name recognition and to establish herself in academic nephrology. Dr. Simic’s long-term career goal is to become an independent physician-scientist and a leading expert in kidney-bone interactions and mineral metabolism. She will benefit from complementary mentorship from Eugene Rhee (primary mentor; Chief, MGH Adult Nephrology), an expert in kidney metabolism, and Harald Jueppner (co-mentor, Chief, MGH Pediatric Nephrology), a leader in mineral biology. Dr. Simic’s career development plan will capitalize on the training and scientific resources in the MGH Nephrology Division and Endocrine Unit, as well as Harvard Medical School. Drs. Simic, Rhee and Jueppner will meet frequently to discuss both science and career development, and have clearly identified aspects of the research proposed that will form the basis of her independent career. An advisory committee has been formed to evaluate progress, provide additional guidance, and plan future directions. Dr. Simic will present her data regularly both in the MGH Nephrology Division and Endocrine Unit and will be supported to present her work at national meetings. Formal coursework is planned in grant writing, public speaking, responsible conduct of research, bioinformatics, metabolomics, and drug development to further enhance her probability of success as an independent physician/scientist.