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。

基本信息

  • 批准号:
    10320973
  • 负责人:
  • 金额:
    $ 17.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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)是一种骨源性激素,通过以下途径控制血磷水平 增加肾脏磷酸盐排泄,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而增加,是不良肾脏结局的强烈独立危险因素 死亡率。然而,对FGF23产生的调节因素缺乏基本的了解。 我们对FGF23合成的肾脏介体进行了代谢组/蛋白质组筛选,并发现 发现了一个新的信号轴,通过它肾脏衍生的甘油-3-磷酸(G-3-P)被转化为 骨骼中的溶血磷脂酸(LPA),然后刺激FGF23的合成。本提案的重点就是这一点 LPA的新作用,中心假设LPA通过LPA受体1介导信号传递 在急性肾损伤(AKI)中,LPAR1对FGF23的产生起关键作用。在强劲的初步数据支持下,我们 将使用Lpar1基因敲除小鼠来分析这一途径,以响应外源LPA注射(AIM 1)和实验性AKI(目标2)。总之,这些研究试图建立LPA和LPAR1作为潜在的 FGF23介导的肾脏疾病发病率和死亡率的治疗靶点,并作为 在肾脏病和新陈代谢的交叉点上,迈向独立的科学生涯的跳板。 候选人西米克博士致力于肾脏病基础研究的职业生涯。她之前 接受了衰老和骨生物学方面的研究培训,但自2018年完成肾病研究员资格以来, 将她的注意力转移到一个新的领域-肾脏疾病、新陈代谢和FGF23动态平衡。西米奇医生马上 职业目标包括获得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,并在肾脏病学学术领域站稳脚跟。西米奇博士的长期职业目标是 成为一名独立的内科科学家和肾脏-骨骼相互作用和矿物质方面的领先专家 新陈代谢。她将受益于Eugene Rhee(主要导师;MGH首席导师)的补充指导 肾脏新陈代谢专家Harald Jueppner(MGH儿科主任,共同导师 肾脏学),矿物生物学领域的领先者。西米奇博士的职业发展计划将利用这次培训 MGH肾病科和内分泌科以及哈佛医学院的科学资源 学校。Simic、Rhee和Jueppner博士将经常会面,讨论科学和职业发展, 并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事业的基础。 已经成立了一个咨询委员会,以评估进展情况,提供更多指导,并规划未来 方向。西米奇博士将在MGH肾病科和内分泌科定期提交她的数据 并将得到支持,在全国会议上介绍她的工作。正式的课程作业是在助学金写作中计划的, 公开演讲,负责进行研究、生物信息学、代谢组学和药物开发,以 进一步提高她作为一名独立医生/科学家的成功几率。

项目成果

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Petra Simic其他文献

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{{ truncateString('Petra Simic', 18)}}的其他基金

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:
    10542347
  • 财政年份:
    2020
  • 资助金额:
    $ 17.28万
  • 项目类别:
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