STEROID HORMONE REGULATION OF TSH SUBMIT BIOSYNTHESIS

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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.