Specialty: Neuroscience:
Neuroendocrinology
Cell Biology and
Biochemistry: Protein processing and trafficking
The main focus in my laboratory is to study the biology of different neuropeptides involved in the regulation of energy balance, thyroid function and growth hormone axis. The proneuropeptide and peptide hormones currently investigated in my laboratory are, proThyrotropin releasing hormone (proTRH), progrowth hormone-releasing hormone (proGHRH), prooipimelanocortin (POMC) and leptin. We also study the effect that leptin and the norepinephrine system has on the gene transcription and biosynthesis of neuropeptides and on the prohormone convertases (PCs) involved in the post-translational processing of proneuropeptides.
Overview of research programs
Our laboratory has contributed in great
part the current knowledge on the neurobiology of proThyrotropin Releasing
Hormone (proTRH). We have
contributed to a better understanding of how several neuro-endocrine inputs
(norepinephrine, NE, a-melanocyte
stimulating hormone, a-MSH,
neuropeptide Y, NPY) and other hormones (leptin and glucocorticoids) affect
proTRH gene regulation, its biosynthesis and processing. We also promoted the
discovery of novel proTRH-derived peptides with potential biologic function(s).
In physiological models, we have shown the effect that lactation has on
hypothalamic proTRH processing, and discovered a proTRH-derived peptide that is derived from proTRH processing and is capable
of inducing prolactin (PRL) secretion in pituitary cells. We also studied the impact of cold
stress on thermoregulation in the fat/fat mouse, which has a deficient level of hypophysiotropic TRH,
and demonstrated recently that other proTRH-derived peptide increases in the
periaquaductal gray matter during morphine withdrawal. We have developed a
post-translational processing model for proTRH, and demonstrated that PC1 and
PC2 are responsible for the processing of proTRH at specific sites. We also showed that carboxypeptidase E
is the primary enzyme involved in the removal of basic residues after the PC
cleavage. In the rat brain tissues
with high levels of proTRH expression, we showed tissue-specific processing for
different proTRH peptides.
Energy balance
As an adaptive response to starvation, the hypothalamic-pituitary-thyroid axis is down-regulated in rodents. This is caused, at least in part, by suppression of proTRH mRNA expression in the hypothalamus, which can be reversed by leptin. The action of leptin on TRH neurons in the paraventricular nucleus (PVN) of the hypothalamus occurs through an indirect pathway, involving the release of neuropeptides such as NPY, a-MSH and AgRP from arcuate nucleus, and a direct pathway of leptin action on TRH neurons expressing the leptin receptor. In our studies we investigate the molecular and cellular events involved in the action of leptin and a-MSH on the proTRH life cycle. We also study the effect that leptin, a-MSH and NE has on the gene expression and biosynthesis of PC1 and PC2.
Pro-neuropeptide processing
and trafficking
In recent years considerable research has focused on the expression of neuropeptide genes and their tissue-specific regulation. However, it has become clear that the peptides derived from these genes play significant neuromodulatory roles in the control of the central nervous system neurotransmitters. Even more astounding is the discovery that multiple neuropeptides with distinct physiological functions arise from the processing of single polypeptide precursors. The post-translational processing and the intracellular sorting of these precursors are key elements to understand these processes. Our laboratory studies the processing and trafficking of proTRH and proGHRH and the role that PC1 and PC2 play in this process. We also try to identify the intracellular sorting signals and receptors involved in the correct trafficking of secretory proteins to the regulated secretory pathway.
Cold stress and energy
consumption
TRH is essential for the survival of most animals in cold environments and TRH secretion by the hypothalamus is increased during cold. Moreover the NE system plays a crucial role in cold-induced augmentation of TRH secretion and in increased thermogenesis during leptin rise as a response to consume more calories. TRH neurons in the PVN receive dense NE innervations. We study the mechanisms whereby cold and NE enhance mature TRH production through processing of its precursor.
Prolactin
Suckling increases preproTRH mRNA in hypothalamic paraventricular neurons (PVN) and also markedly increases TRH release during the first period of lactation. Our laboratory has recently shown that lactation alters preproTRH processing resulting in the generation of novel proTRH-derived peptides with prolactin secretion activity. We are studying the receptor and signal transduction pathway for these molecules.
Tissue-specific processing
of proTRH in the brain
ProTRH is differentially processed in the brain suggesting distinct roles for TRH and other non-TRH proTRH-derived peptides as neurotransmitters and neuromodulators. We investigate the potential biologic role of these peptides under different physiological conditions.
Projects available: Prothyrotropin releasing hormone processing and sorting
Progrowth hormone releasing hormone processing and sorting
Leptin and other regulatory peptides regulation of the hypothalamic pituitary thyroid axis
Stimulation of prolactin biosynthesis by novel peptides
Selected
Publications:
Harris
M, Aschkenasi C, Elias CF, Chandrankunnel A, Nillni EA, Bjorbaek C,
Nillni EA, Vaslet C, Harris M, Hollenberg A,
Bjorbak C, Flier JS.
Nillni
EA, Sevarino KA. The biology of pro-thyrotropin-releasing hormone-derived
peptides.
Endocr Rev. 1999 Oct;20(5):599-648.
Review.
Nillni
EA. Neuroregulation of ProTRH biosynthesis and
processing.
Endocrine. 1999 Jun;10(3):185-99. Review.