THE ROLE OF ESTROGEN IN BONE METABOLISM

雌激素在骨代谢中的作用

• 批准号: 6387396
• 负责人: Orhan Kemal Oz
• 金额: $ 9.18万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6387396
• 关键词: aging; aromatase; bone development; bone marrow; bone metabolism; cell differentiation; cell proliferation; cytokine; enzyme deficiency; enzyme linked immunosorbent assay; estrogens; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory mouse; musculoskeletal disorder diagnosis; normal ossification; osteoporosis; polymerase chain reaction; skeletal disorder chemotherapy; statistics /biometry; tissue /cell culture

The candidate, Dr. Orhan K. Oz, is a diagnostic radiologist with previous scientific training in biophysics and tumor biology who seeks to become an independent investigator in the field of bone biology. To make this transition additional training will be necessary under the auspices of a career development award. His long-term career goals are to improve understanding of the pathophysiology of osteoporosis and to use this understanding as the basis for new therapeutic and diagnostic modalities for this disease. A development plan has been developed in which the candidate will conduct research on the role of estrogen in bone metabolism under the guidance of Drs. Zerwekh and Sakhaee experienced investigators in the field of bone biology. They will direct the basic science and clinical activities necessary for this project. Dr. Oz will become an active participant in data conferences and the local Bone Research Society - activities and an environment designed to enhance the candidate's transition to the field of bone science. The broad, long-term objective of the research is to elucidate the mechanisms of estrogen's effect on bone growth and metabolism and to use that information to develop new therapeutic and diagnostic modalities for osteoporosis. The enzyme aromatase synthesizes estrogen from its androgen precursors. Estrogen withdrawal in post-menopausal women is associated with an increase of bone turnover and acceleration of bone loss, that leads to an increased susceptibility to bone fractures and clinically relevant osteoporosis in one third of all women. The recent observation of a phenotype in men with aromatase deficiency or estrogen receptor deficiency comprising failure of epiphyseal fusion closure leading to excessive height together with osteopenia, is indicative of an important role of estrogen in bone growth and metabolism of males, as well as females. This leads to the issue of the origin of the estrogen involved in the bone metabolism and points to the possibility that local formation of estrogen within bone tissues may play an important role in bone mineral metabolism in both sexes. The central hypothesis is that estrogen is an important regulator of growth and metabolism which effects its regulatory function by influencing bone cell differentiation and the differentiated function of bone cells. A model of estrogen deficiency has recently been created, namely the aromatase-deficient (ArKO) mouse. Specific aims designed to test this hypothesis are: 1) To study the cellular distribution of aromatase in sections of bone tissue from mice of various ages; 2) To study bone metabolism in the ArKO knock-out mouse; 3) To determine whether aromatase deficiency affects bone cell differentiation and proliferation and; 4) To study expression of cytokines, critical to bone growth and metabolism, in bone marrow cells from aromtase deficient mice.

候选人奥尔罕·K博士奥兹是一名诊断放射科医生，曾接受过生物物理学和肿瘤生物学方面的科学培训，他希望成为骨生物学领域的独立研究者。 为了实现这一过渡，将需要在职业发展奖的赞助下进行额外的培训。 他的长期职业目标是提高对骨质疏松症病理生理学的理解，并将这种理解作为这种疾病新的治疗和诊断方式的基础。 已经制定了一项发展计划，其中候选人将在Zerwekh博士和Sakhaee博士的指导下，在骨生物学领域经验丰富的研究人员的指导下，对雌激素在骨代谢中的作用进行研究。 他们将指导该项目所需的基础科学和临床活动。 奥兹博士将成为数据会议和当地骨研究协会的积极参与者-旨在促进候选人向骨科学领域过渡的活动和环境。 这项研究的广泛、长期目标是阐明雌激素对骨生长和代谢的作用机制，并利用这些信息开发新的骨质疏松症治疗和诊断方法。 芳香化酶从雄激素前体合成雌激素。 绝经后妇女的雌激素戒断与骨转换增加和骨丢失加速有关，这导致三分之一的妇女对骨折和临床相关骨质疏松症的易感性增加。 最近在患有芳香酶缺乏或雌激素受体缺乏的男性中观察到的表型包括骨骺融合闭合失败，导致过高以及骨质减少，这表明雌激素在男性以及女性的骨生长和代谢中具有重要作用。 这就引出了参与骨代谢的雌激素的来源问题，并指出骨组织内雌激素的局部形成可能在两性的骨矿物质代谢中发挥重要作用。 中心假设是雌激素是生长和代谢的重要调节剂，通过影响骨细胞分化和骨细胞的分化功能来影响其调节功能。 最近建立了雌激素缺乏的模型，即芳香化酶缺乏（ArKO）小鼠。 为验证这一假设而设计的具体目标是：1）研究芳香化酶在不同年龄小鼠骨组织切片中的细胞分布; 2）研究ArKO敲除小鼠的骨代谢; 3）确定芳香化酶缺乏是否影响骨细胞分化和增殖; 4）研究芳香化酶缺陷小鼠骨髓细胞中对骨生长和代谢至关重要的细胞因子的表达。