University of Toronto Logo - Physiology

RESEARCH

• Neuronal cell biology, focusing on the mechanisms of neuron-specific gene expression
• Regulation of gonadotropin-releasing hormone gene expression and secretion by gonadal steroid   hormones in hypothalamic cell culture
• Regulation of afferent neurons to the GnRH neuron by hormones
• Signal transduction pathways and transcriptional mechanisms involved in the control of neuropeptides involved in energy homeostasis - gene expression and secretion
• Role of nutrients on circadian rhythm proteins in specific peptide-expressing hypothalamic neurons
• Development of clonal, immortalized, hypothalamic neuronal and glial cell lines
• Characterization of novel hypothalamic cell lines developed in my laboratory

Overview of Dr. Belsham’s Research Program:
The main focus of my laboratory is to understand, at the molecular level, how the hypothalamus achieves its diverse physiological functions. The neuroendocrine hypothalamus consists of a complex array of distinct neuronal phenotypes, each expressing a specific complement of neuropeptides, neurotransmitters and receptors. Many of our vital needs, such as those for growth, reproduction, nutrition, sleep, and stress responses, depend on hormonal balance or homeostasis, which is controlled by both external and internal stimuli or signals at the hypothalamic level.

A) Regulation of GnRH Neurons and Afferent Control Mechanisms:
In order to begin to dissect the molecular signals responsible for the release of specific peptides from individual hypothalamic neurons, my laboratory has focussed on the peptide that controls reproduction, gonadotropin-releasing hormone or GnRH. A large number of neuromodulators have been implicated in the control of reproductive function, as they have been found to regulate GnRH synthesis and secretion. My research program studies many aspects of GnRH function, and how afferent neurons affect the GnRH neurons. We also study the direct regulation of these afferent neurons, such as kisspeptin, neuropeptide Y, and gonadotropin inhibitory hormone, by steroids and other peripheral signals.

B) Generation and Characterization of Hypothalamic Cell Models:
We therefore analyze the direct actions of neuromodulators on individual GnRH neurons; the transcriptional mechanisms dictating the neurogenesis of individual hypothalamic neurons; and the development of specific immortalized hypothalamic neuronal cell models in order to understand the molecular mechanisms involved in interneuron communication and signaling. To address this last point, my laboratory has recently generated a number of cell models representing other specific cell types from the hypothalamus. These models have been used by many labs worldwide to understand how hypothalamic neurons function. These models include embryonic- and adult-derived cell models from the mouse and rat, and represent the many cell types found in the hypothalamus and hippocampus.

C) Analysis of the Neuropeptides involved in Energy Homeostasis:
We have a strong track record of neuroendocrine research, and have also expanded our research program to include the study of neuropeptides involved in both reproduction and energy homeostasis. Currently half of my research efforts are directed towards studies related to the function of the GnRH and afferent neurons, such as kisspeptin, neuropeptide Y and ganadotropin inhibitory hormone, and the other half has extended our research program to include studies of many of the neuropeptide-expressing neurons involved in energy homeostasis. These include neuropeptide Y, neurotensin, brain ghrelin, corticotropin-releasing hormone, and proopiomelanocortin. We are currently analyzing the changes in gene expression and signal transduction events after exposure to key peripheral signals such as insulin, ghrelin, glucose, leptin, and estrogen. Importantly, there is also a direct relationship between nutritional status and reproduction, therefore my research program is poised to utilize all the information gained to provide insight into the complex nature of integrated neuroendocrine control of basic physiology.

METHODS USED

Cell and tissue culture: Neurons

Procedures: Cell biology techniques, cell line generation, cell culture, gene expression analysis, in-vivo hypothalamus immunocytochemistry, microarrays, molecular biology techniques, proteomics, signal transduction characterization

SAMPLE PUBLICATIONS AND ABSTRACTS:

PRESENT TRAINEES

PRESENT COLLABORATIONS

Outside the Department of Physiology:
David Lovejoy, Cell and Systems Biology, U of T
Martin Ralph, Psychology/Cell and Systems Biology, U of T
Abhiram Sahu, University of Pittsburg, USA
Debbie Good, Viginia Tech, USA
Pamela Mellon, UCSD, USA
Alexander Kaufmann, UCSD, USA
Rob Fowkes, Univ of London, UK
Holly Ingraham, UCSF, USA
Charles Mobbs, Mt Sinai Sch of Med, NY, USA