PHOSPHOTONIN--A NOVEL PHOSPHATE REGULATORY HORMONE

磷酸素--一种新型磷酸盐调节激素

• 批准号: 6176007
• 负责人: SUZANNE M JAN DE BEUR
• 金额: $ 12.57万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6176007
• 关键词: bone metabolism; genetically modified animals; hormone regulation /control mechanism; hormones; laboratory mouse; molecular cloning; osteomalacia; phosphorus metabolism; protein structure function; radioimmunoassay; vitamin D resistant rickets

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.

作为一名发展中的内科科学家，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和疾病过程的基本理解转化为床边。我致力于学术医学的事业，目标是发展国际公认的磷酸盐动态平衡。这项提案中概述的研究将使我能够通过扩大我在蛋白质生物化学、转基因技术和抗体以及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。深入的实验室研究将通过细胞和分子医学项目的课程工作来补充。约翰霍普金斯医学院为机构一级和莱文实验室的合作和技术支持提供了丰富的环境。迈克尔·莱文博士是一位国际公认的骨骼和矿物质代谢专家，在指导方面有着良好的记录。他是约翰霍普金斯大学机构医生科学家奖的前任主任，现在是细胞和分子内分泌学培训项目的主任。莱文博士和我设计的其他有指导的实验室工作和具体的职业发展计划将为我提供开始独立研究生涯所需的技能。我准备的研究提案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。致癌性骨软化(OOM)是一种以低磷血症、低磷尿和骨软化为特征的副肿瘤性综合征。与OOM相关的肿瘤分泌一种名为磷酸素(PTN)的因子，该因子可抑制肾近端小管对磷酸盐的重吸收。X-连锁低磷血症性软骨病是一种临床表现类似于OOM的遗传综合征。XLH中的缺陷基因编码PEX，一种膜结合的金属多肽酶。这一类中的其他酶在激素的处理和降解中起着重要的作用。有缺陷的PE酶的发现，再加上XLH和OOM中循环中的磷酸因子的证据，导致了对PEX和PTN关系的猜测。我们假设，磷脂素对骨骼中的磷酸盐稳态很重要，一旦磷脂素进入血液循环，它就会对近端肾小管起到磷酸尿酸的作用。磷酸被释放到循环中的方式有两种，一种是异位产生，如OOM，另一种是不能被灭活，如XLH。我们建议：1)分离磷脂素；2)确定PEX在磷酸盐稳态中的作用及其与磷脂素的相互作用；3)确定磷脂素在正常生理和磷酸盐稳态紊乱中的作用。鉴定和鉴定磷酸化激素将有助于理解磷酸盐稳态，进一步确定X连锁低磷血症性软骨病的遗传缺陷，并鉴定一种新的在致癌性骨软化症中异位产生的激素。