Thesis--Ph. D., University of Hong Kong. / Typewritten.

Thesis--Ph. D., University of Hong Kong. / Typewritten.

Thesis--Ph. D., University of Hong Kong. / Typewritten.

Thesis--Ph. D., University of Hong Kong, 1981.

Thesis (Ph. D.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 171-212).

Thesis (M.D.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 207-261).

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: juvenile hormone; Limulus; horseshoe crab. Includes bibliographical references (p. 68-79).

published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

Evidence suggests that thyroid hormone acts by binding to nuclear receptors which regulate expression of a discrete number of proteins, including cardiac ventricular myosin isoenzymes. Administration of thyroid hormone is known to stimulate synthesis of ventricular α-myosin heavy chain and inhibit production of a (beta)-myosin heavy chain. The first part of this study examines the effects of naturally occurring and synthetic thyroid analogs, catecholamines and high carbohydrate diets on ventricular myosin isoenzyme expression in thyroidectomized and hypophysectomized rats. Also, the effects on myosin isoenzyme expression of adrenalectomy and hydrocortisone replacement have been studied in euthyroid animals. Myocardial CO₂ production and hepatic α-glycerol phosphate dehydrogenase activity were measured to monitor the effects of these interventions on tissue respiration. The results indicate that thyroid hormone analogs do not selectively stimulate myosin isoenzyme expression as compared with their effects on energy production. No significant separation between the actions of these analogs on metabolic parameters and myosin isoenzyme patterns was found. However, high carbohydrate feeding in thyroidectomized and hypophysectomized rats increased the content of the α-myosin heavy chain. β-Adrenergic stimulation with isoproterenol and blockade with propranalol did not affect myosin isoenzyme expression. Adrenalectomy in euthyroid rats decreased the α-myosin heavy chain with a corresponding increase in the β-myosin heavy chain. This could be reversed by treatment with hydrocortisone. The results suggest that the mechanism for regulation of cardiac myosin isoenzymes may involve a primary signal related to dietary carbohydrate, which is modulated by thyroid hormone, and possibly glucocorticoids. The method for purification of the T₃-receptor-DNA complex is described. This complex is thought to mediate the action of T₃ on gene expression. The results indicate that a relatively pure form of an intact receptor-DNA complex (M.W. 111,000) can be isolated from a T₃-affinity gel. Only a single protein component (M.W. 58,000) was identified by electrophoresis and coomasie blue staining of the purified complex. The associated double stranded DNA fragment (M.W. 52,000) was estimated to contain about 88 basepairs. This complex could be dissociated by treatment with 0.4 M KCl or DNase I, but did not undergo spontaneous exchange with exogenous labeled DNA fragments. Equilibrium binding studies demonstrated a single class of high affinity T₃-binding site with a dissociation constant (50 pM) which was significantly lower than that of the micrococcal digest (1.1 nM).

published_or_final_version / Medicine / Master / Doctor of Medicine