The long term goals of this program are to elucidate mechanisms of control of thyrotropin-releasing hormone (TRH)-producing neurons in the hypothalamic paraventricular nucleus (PVN) that comprise a critical component of the hypothalamic-pituitary-thyroid (HPT) axis, and to determine how these neurons alter their response to feedback signals by thyroid hormone during adaptive and pathological conditons that give rise to the nonthyroidal illness syndrome observed in man. The possibility that the monocarboxylate transporter 8 (MCT8) and steroid receptor co-activator (SRC-1) contribute to feedback regulation of hypophysiotropic TRH will be explored in transgenic mice in which MCT8 or SRC-1 is selectively removed from TRH-producing cells. Mechanisms whereby leptin, AGRP, and a-MSH regulate TRH neurons in the PVN during fasting and refed states will be studied in the neuronal selective POMC KO mouse and by using transgenic mice that express Cre recombinase selectively in TRH-producing cells. We will further study the role of AMP-activated protein kinase to mediate inhibitory effects of AGRP on hypophysiotropic TRH and the importance of glutamate/ cannabinoid interactions as a mechanism involved in fasting-induced suppression the HPT axis. The importance of the hypothalamic dorsomedial nucleus (DMN) as a metabolic sensor for TRH neurons in the PVN will be explored, and the hypothesis tested that the DMN integrates signals from the arcuate nucleus and subparaventricular zone that are responsible for the circadian periodicity of the HPT axis. Mechanisms by which endotoxin suppress the HPT axis will be studied, focusing on effects mediated by the cAMP-response element modulator (CREM), inducible cAMP early represser (ICER) and/or corticotropin-releasing hormone (CRH). We will also determine whether LPS-induced activation of type 2 iodothyronine deiodinase (D2), an enzyme critical for conversion of thyroxine (T4) into its active form triiodothyronine (T3) and highly expressed in tanycytes, downregulates the HPT axis by increasing local tissue levels of T3. Finally, we will explore the possibility that in addition to the central effects on hypophysiotropic TRH neuronal cell bodies, endotoxin has a dual inhibitory effect on TRH neurons as a result of inducing morphologic rearrangement of tanycyte endfeet processes in association with TRH-containing axon terminals in the external zone of the median eminence.
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