NSF Award
9810349
IBN-9810349 Nillni Rat thyrotropin-releasing hormone (TRH) produced in the paraventricular nucleus of the hypothalamus (PVN) was first shown to stimulate the biosynthesis and secretion of the thyrotropin-stimulating hormone (TSH) from the anterior pituitary, which in turn regulates thyroid function. This effect showed to play a central role in regulating the pituitary-thyroid axis. This hormone derives from a larger protein precursor (proTRH). ProTRH also encodes seven intervening peptides with potential biological activity. An understanding of the biosynthesis and biochemical processing of proTRH is critical to appreciating how, when and where regulation of the hypothalamic-pituitary-thyroid (HPT) axis takes place during physiologically appropriate enhancement of thyroid function. ProTRH is widely expressed throughout the brain and spinal cord, in particular the PVN and ventrolateral medulla. In the last few years, our laboratory has made substantial contributions to understanding how TRH is synthesized, by demonstrating the way proTRH is processed, and by finding the proteolytic enzymes involved in this process. In spite of our knowledge of proTRH biosynthesis and processing, little is known about the physiological regulation of proTRH biosynthesis and processing, and the neuronal factors involved in this regulation. TRH is integral to the survival of most animals in cold environments and TRH secretion by the hypothalamus is increased during cold. Moreover the noradrenergic (NE) system plays a crucial role in cold-induced augmentation of TRH secretion. TRH neurons in the PVN receive a dense NE innervation. However, the mechanisms whereby cold and NE enhance mature TRH production are unknown, but could be due to enhancement of proTRH biosynthesis or processing. Data are scant regarding the regulation of the enzymes involved in this activity in the brain during physiological or pharmacological situations where TRH and HPT axis activity is stimulated. Therefore, in these studies it will be investigated the role that the processing enzymes play in the processing of proTRH. It will be also determine the generation of TRH during physiological activation of the HPT axis. Cold represents a strong stimulus to the activation of the HPT axis and represents a more chronic response where adaptive changes in the processing of proTRH are necessary. In addition, the genesis of TRH will be examined in cold- exposed enzyme deficient knockout mice. Cold-induced TRH release is mediated by activation of brain NE systems. Therefore, it will be examine in normal and cold-exposed mice and rats whether the activation of NE systems mediate these effects. There are virtually no data available on the regulation of prohormone processing in the brain. These studies will provide novel information on the physiological and environmental regulation of proTRH processing in PVN neurons regulating the HPT axis.
