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

溶血磷脂酸 (LPA) 是急性肾损伤中的一种新型 FGF23 调节剂。

• 批准号: 10320973
• 负责人: Petra Simic
• 金额: $ 17.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320973
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Advisory Committees; Affect; Aging; Applications Grants; Area; Attenuated; Bioinformatics; Biology; Blood; Blood Circulation; C-terminal; CRISPR/Cas technology; Calcium; Calvaria; Chemicals; Childhood; Chronic Kidney Failure; Cisplatin; Data; Development Plans; Dose; Endocrine; Excretory function; Fellowship; Future; G-Protein-Coupled Receptors; Gene Expression; Goals; Grant; Histology; Homeostasis; Hormones; Immunohistochemistry; Inflammation; Injections; Injury to Kidney; Investigation; Iron; Kidney; Kidney Diseases; Knockout Mice; LPAR4 gene; Laboratories; Lysophosphatidic Acid Receptors; Manuscripts; Measures; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolism; Minerals; Modeling; Morbidity - disease rate; Mus; Names; Nephrology; Osteoblasts; Osteocytes; Outcome; Outcome Measure; Pathway interactions; Physicians; Plasma; Probability; Production; Prognosis; Proteins; Proteomics; Public Speaking; Publishing; Renal function; Reperfusion Injury; Research; Research Personnel; Research Training; Resources; Risk Factors; Role; Science; Scientist; Serum; Signal Pathway; Signal Transduction; Specificity; Testing; Time; Tissues; Training; Translating; Urine; Work; Writing; alpha-glycerophosphoric acid; bone; career; career development; drug development; experimental study; fibroblast growth factor 23; inhibitor; inorganic phosphate; insight; kidney metabolism; liquid chromatography mass spectrometry; lysophosphatidic acid; medical schools; meetings; metabolomics; mortality; mortality risk; multidisciplinary; new therapeutic target; novel; novel therapeutics; receptor; renal ischemia; response; responsible research conduct; rho; skills; success; therapeutic target; training opportunity; transcriptome sequencing; urinary; vzg-1 Receptor

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.

项目摘要/摘要 成纤维细胞生长因子23（FGF23）是一种骨衍生的激素，可通过控制血液磷酸盐水平 增加肾磷酸盐排泄并减少1,25-二羟基维生素D3的产生。 FGF23水平 随着肾脏疾病的增加，是不良肾脏结局的强大独立危险因素， 死亡。但是，缺乏对FGF23生产的调节的基本了解。 我们为FGF23合成的肾脏介质进行了代谢组/蛋白质组学筛选，并具有 确定了一个新的信号轴，肾脏衍生的甘油-3-磷酸甘油（G-3-P）被转换为 骨骼中的溶血磷脂酸（LPA），然后刺激FGF23合成。该提案重点是 LPA的新作用，中心假设是LPA通过LPA接收器介导的信号传导1 （LPAR1）对于急性肾损伤（AKI）中FGF23产生至关重要。在强大的初步数据的支持下，我们 将使用LPAR1基因敲除小鼠响应外源性LPA给药（AIM）来剖析这一途径 1）和实验性AKI（AIM 2）。这些研究共同试图将LPA和LPAR1作为潜力建立 FGF23介导的肾脏疾病中介导的发病率和死亡率的治疗靶标，并充当 在肾脏病和代谢的交集的独立科学职业的跳板。 候选人Simic博士致力于从事肾脏科基础调查的职业。她以前 从事衰老和骨骼生物学的研究培训，但是自从在2018年完成肾脏病研究金以来 将她的注意力转移到了一个新的领域 - 凯尼疾病，代谢和FGF23稳态。 Simic博士的立即 职业目标包括获取本赠款提案中描述的技能和出版第一作者手稿 获得名称识别并在学术肾脏学中建立自己。 Simic博士的长期职业目标是 成为独立的身体科学家和肾脏互动和次要的领先专家 代谢。她将受益于尤金·瑞（Eugene Rhee）的完全心态（主要心理；负责人，MGH 成人肾脏病），肾脏代谢专家和Harald Juepppner（联合，首席，MGH儿科 肾脏科），矿物质生物学的领导者。 Simic博士的职业发展计划将利用培训 MGH肾脏病和内分泌部门的科学资源以及哈佛医学 学校。博士。 Simic，Rhee和Jueppner将经常见面，讨论科学和职业发展， 并清楚地确定了提出的研究的各个方面，这些方面将构成她独立职业的基础。 已经成立了一个咨询委员会来评估进度，提供其他指导并计划未来 方向。 Simic博士将定期在MGH肾脏科和内分泌部门介绍她的数据 并将支持她在国家会议上介绍她的工作。计划在赠款写作中计划正式课程， 公开演讲，负责任的研究，生物信息学，代谢组学和药物开发 进一步提高了她作为独立身体/科学家成功的可能性。