STEROID HORMONE REGULATION OF TSH SUBMIT BIOSYNTHESIS

类固醇激素对 TSH 提交生物合成的调节

• 批准号: 3080483
• 负责人: DOUGLAS S ROSS
• 金额: $ 7.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1988-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3080483
• 关键词: cell free system; dimer; estrogens; genetic regulation; genetic transcription; glucocorticoids; hormone regulation /control mechanism; hormone related neoplasm /cancer; male castration; messenger RNA; pituitary neoplasms; radioimmunoassay; radiotracer; sex hormones; testosterone; thyrotropin

The major regulator of TSH is thyroid hormone (negative feedback). The glucocorticoid and sex steroid hormones are also important modulators of TSH. TSH is a dimer composed of an Alpha-subunit which it shares with several other hormones, and a specific Beta-subunit. These subunits are synthesized from separate mRNAs, which suggest fundamental questions concerning their coordinate or non-coordinate regulation. The applicant's prior research documented discordant regulation of TSH-Beta and Alpha by thyroxine. Glucocorticoid inhibition of TSH may occur via a mechanism similar to that of the thyroid hormones. Following in vivo treatment with glucocorticoids, mice bearing thyrotropic tumors, a tissue containing only thyrotropes derived from hypothyroid pituitary, will be killed and analyzed for plasma, pituitary, and tumor TSH and subunit concentrations by specific RIAs. RNA will be isolated for determination of steady-state levels of mRNA for Alpha and TSH-Beta by hybridization to specific cDNA probes. Transcription rates, mRNA stability, and translation products of mRNAs will be measured, and the possibility of noncoordinate subunit regulation will be explored. Testosterone inhibits synthesis of LH and the common Alpha-subunit which LH shares with TSH. There is only one copy of the Alpha gene. In the mouse, testosterone increases plasma TSH concentration; if testosterone also increases thyrotrope Alpha synthesis, this suggests that the effects of testosterone Alpha is cell specific (thyrotrope vs gonadotrope). Measurement of protein and mRNA concentrations in thyrotropic tumors and castrate pituitaries (a gonadotrope enriched tissue) will address fundamental questions concerning cell-specific regulation of a single gene. Protocols using estrogen will address similar questions. Dr. Ross, a graduate of Harvard Medical School, completed his internal medicine and endocrine training at Mass. General Hospital where he has been a research trainee in the Thyroid Unit since July 1981. His basic research on discordant regulation of TSH subunit biosynthesis has yielded 5 publications to date (1 pending) of which he is first author on 3. Additionally, he has completed 3 clinical projects. He plans an academic career with emphasis on basic research. The Thyroid Unit at Mass. General Hospital provides an outstanding environment for a young investigator. There is broad-based expertise within the laboratory, as well as outstanding laboratories using the most up-to-date techniques in molecular biology and molecular genetics available for consultation within the hospital.

TSH的主要调节因子是甲状腺激素（负反馈）。 的 糖皮质激素和性类固醇激素也是 促甲状腺激素 TSH是一种由α亚基组成的二聚体， 其他几种激素和一种特定的β亚基 这些亚单位是 由不同的mRNA合成，这就提出了一些基本问题， 关于它们的协调或非协调调节。 申请人的 先前的研究记录了TSH-β和α的不协调调节， 甲状腺素。 糖皮质激素对TSH的抑制作用可能通过类似于 甲状腺激素的变化。 在用糖皮质激素进行体内治疗后， 携带促甲状腺肿瘤的小鼠，一种仅含有促甲状腺细胞的组织 来源于甲状腺功能减退的垂体，将被杀死并分析血浆， 垂体和肿瘤TSH和亚单位浓度的特定RIA。 RNA 将被分离用于确定α mRNA的稳态水平 和促甲状腺激素β通过杂交到特定的cDNA探针。 转录 将测量mRNA的速率、mRNA稳定性和翻译产物， 并探讨非协调亚基调控的可能性。 替吉奥抑制LH和与LH共同的α亚单位的合成， 分享TSH 阿尔法基因只有一个拷贝。 在老鼠体内， 睾酮增加血浆TSH浓度;如果睾酮也 增加促甲状腺激素α的合成，这表明， 睾酮α是细胞特异性的（促甲状腺激素对促性腺激素）。 促甲状腺肿瘤中蛋白质和mRNA浓度的测量， 阉割垂体（富含促性腺激素的组织）将解决 关于细胞特异性调节单个 基因 使用雌激素的方案将解决类似的问题。 博士罗斯毕业于哈佛医学院， 医学和内分泌训练他去过的综合医院 自1981年7月以来一直在甲状腺科做研究实习生。 他的基础研究 对TSH亚基生物合成的不协调调节的研究已经产生了5 迄今为止的出版物（1项待定），其中3项是他的第一作者。 此外，他还完成了3个临床项目。 他计划一个学术 以基础研究为重点的职业。 甲状腺单位在质量。一般 医院为年轻的研究人员提供了一个良好的环境。 实验室拥有广泛的专业知识， 在分子生物学领域使用最先进技术的优秀实验室 生物学和分子遗传学可供咨询 医院