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900 Walnut St. (215) 955-0580 |
Gregory E. Gonye, PhD|
How Do Neuropeptides Chage Gene Expression in CNS Neurons, Leading to Hypertentsion? Neuropeptides, a class of very small proteins, act at highly selective receptors located in the cellular membranes of many different cell types. Neuropeptides are involved in nearly all medically important physiological processes and are best known for their role in blood pressure regulation, sleep, pain, appetite, stress, libido, drug addiction, and depression. My research uses the study of neuropeptide receptor-dependent transcription regulation networks in an attempt to understand how neuropeptides modulate neuronal function and how neurons distinguish one neuropeptide from another with such very high fidelity even though they share the same signaling apparatus in many cases. We use a system level approach that incorporates highly parallel gene expression measurements (using microarrays), transcription factor studies (chromatin immunoprecipitation) and computational approaches including bioinformatics (regulatory network prediction) and modeling and simulation. Our current focus is on the transcriptional response of neurons involved in blood pressure regulation expressing the AT1 receptor for angiotensin II. Activation of this receptor causes changes in gene regulation. We hypothesize that a small panel of transcription factors acting in a network of genes leads to alterations in how these neurons integrate information. To test this hypothesis we apply transcriptional regulatory network analysis (TRNA). TRNA exploits the ability to obtain genomic scale datasets from model systems with sequenced genomes. The genomic sequence allows us to find the regulatory regions of genes which are altered by our manipulations and to analyze these regions as a set. We have developed a number if bioinformatics tools to assist in this effort, collected under the nameplate of Promoter Interaction Analysis Network Toolset or ³PAINT². Hypotheses generated from TRNA are both tested at the bench and used to construct predictive models of the response at the molecular level. This combination of experimental and computational approaches will allow us to better understand the neuronal control of blood pressure and what goes wrong leading to hypertension. |
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