PHOSPHOTONIN--A NOVEL PHOSPHATE REGULATORY HORMONE

作为一名发展中的医生科学家，我的职业目标是培养和整合我作为临床医生和研究人员的经验，以便我最终可以将对正常生理学和疾病过程的基本理解转化为临床实践。我致力于学术医学的职业生涯，目标是发展国际公认的磷酸盐稳态。本计划书中概述的研究将使我能够通过扩大我在蛋白质生物化学，转基因技术以及抗体和放射免疫分析开发方面的经验，将我的临床和技术培训应用并扩展到一个新的水平。密集的实验室研究将通过细胞和分子医学课程的课程工作来补充。约翰霍普金斯医学研究所提供了一个丰富的合作和技术支持，无论是在机构层面和莱文实验室内的环境。Michael Levine博士是国际公认的骨和矿物质代谢专家，拥有强大的指导记录。他是约翰霍普金斯机构医师科学家奖的前任主任，他是细胞和分子内分泌学培训计划的现任主任。莱文博士和我设计的额外的实验室指导工作和具体的职业发展计划将为我提供开展独立研究职业所需的技能。我准备的研究计划是我对激素作用的分子基础、异位激素产生和磷酸盐稳态调节的临床兴趣的延伸。癌源性骨软化症（OOM）是一种以低磷酸盐血症、低磷酸盐尿和骨软化为特征的副肿瘤综合征。与OOM相关的肿瘤分泌一种称为磷酸激素（PTN）的因子，其抑制肾近端小管对磷酸盐的重吸收。X连锁低磷血症性佝偻病（XLH）是一种遗传综合征，临床表现与OOM相似。XLH中的缺陷基因编码PEX，一种膜结合金属肽酶。这类酶中的其他酶在激素加工和降解中具有重要作用。缺陷PE酶的发现与XLH和OOM中循环磷酸尿因子的证据配对，导致了对PEX和PTN关系的推测。我们假设，磷酸激素是重要的磷酸盐稳态在骨骼中，一旦磷酸激素是相关的进入循环，它会产生磷酸尿效应的近端肾小管。磷酸肽通过异位产生（如OOM中）或未能失活（如XLH中）而释放到循环中。我们建议：1）分离磷酸激素2）确定PEX在磷酸盐稳态中的作用及其与磷酸激素的相互作用3）确定磷酸激素在正常生理学和磷酸盐稳态紊乱中的作用。识别和表征磷酸化激素将大大有助于了解磷酸盐稳态，进一步确定X连锁低磷血症性佝偻病的遗传缺陷，并确定一种新的激素产生异位致癌性骨软化症。

As a developing Physician Scientist, my career goal is to cultivate and integrate my experience as a clinician and investigator so that I may ultimately translate a basic understanding of normal physiology and the disease process to the bedside. I am committed to a career in academic medicine with the goal of developing an internationally recognized phosphate homeostasis. The studies outlined in this proposal will allow me to apply and extend my clinical and technical training to a new level by broadening my experience in protein biochemistry, transgenic technology and antibody and radioimmunoassay development. Intensive laboratory investigation will be complimented by course work in the program of Cellular and Molecular Medicine. The Johns Hopkins Medical Institute provides a rich environment for collaboration and technical support both at an institutional level and within the Levine laboratory. Dr. Michael Levine is an internationally recognized expert in bone and mineral metabolism with a strong mentorship track record. He is the previous Director of the Johns Hopkins Institutional Physician Scientist Award and he is the current Director of the Training Program in Cellular and Molecular Endocrinology. Additional mentored laboratory based work and the specific career development plan Dr. Levine and I have devised will provide me with the skills I need to launch an independent research career. The research proposal I have prepared is an extension of my clinical interest in the molecular basis of hormone action, ectopic hormonal production and the regulation of phosphate homeostasis. Oncogenic osteomalacia (OOM) is a paraneoplastic syndrome characterized by hypophosphatemia, hypophosphaturia and osteomalacia. Tumors associated with OOM secrete a factor, termed phosphatonin (PTN) that inhibits renal proximal tubular reabsorption of phosphate. X-linked hypophosphatemic rickets (XLH) is a genetic syndrome with clinical manifestations similar to OOM. The defective gene in XLH encodes PEX, a membrane bound metallopeptidase. Other enzymes in this class have important roles in hormonal processing and degradation. The discovery of the defective PE enzyme paired with evidence for a circulating phosphaturic factor in both XLH and OOM, has led to speculation about the relationship of PEX and PTN. We hypothesize that phosphatonin is important for phosphate homeostasis in the bone and once phospatonin is related into the circulation, it exerts a phosphaturic effect on the proximal renal tubule. Phosphatonin is released into the circulation by either being produced ectopically as in OOM or by failing to be inactivated as in XLH. We propose to: 1) Isolate phosphatonin 2) Determine the role of PEX in phosphate homeostasis and its interaction with phosphatonin 3) Define the role of phosphatonin in normal physiology and in disorders of phosphate homeostasis. Identifying and characterizing phosphatonin will contribute substantially to the understanding of phosphate homeostasis, further define the genetic defect in X-linked hypophosphatemic rickets, and identify a novel hormone produced ectopically in oncogenic osteomalacia.