The Markey Scholars Conference Proceedings (2004) / Chapter Skim
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5 Functional Genomics
Pages 29-41
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Papers Presented by Markey Scholars
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I have to give you a little background for this. My parents were Greek immigrants whose lives were interrupted by World War II and the subsequent civil war against communism in Greece.
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Our initial focus at Regeneron was to identify master regulatory genes involving biological processes with potential therapeutic value, such as neurotrophic growth factors, cytokines, peptide hormones, and their receptors. From the beginning what we were doing is what is now called "functional genomics." We also do subtractive hybridization, or what is now called "differential display and microarrays." We realized from the beginning that these sorts of platforms produced a lot of candidates.
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I want to quickly describe some of the fruits of this technology, and show you how we can get rather dramatic, exciting data. Our goal is therapeutically interesting targets that we can eventually address to human diseases, and do translational research.
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A fourth gene has an incredibly restricted expression pattern in a single layer of neurons in the dorsal part of the spinal cord. These are neurons that sense pain, a perfect place you might want for a pain target.
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We have started to put genes into classes. If we have 5 or 10 secreted proteins or their receptors that are all expressed in cartilage, we can determine if they are only expressed in cartilage or if they are actually critical master regulators of the process in which they are seemingly expressing their specificity.
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I will now describe the discovery of a family of angiogenic factors, not only necessary but also absolutely critical for normal blood vessel formation. Instead of getting normal blood vessels patterning, when you knockout these genes you get this rather nondescript homogenous pattern.
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And we thought, "Hey, these would be perfect candidates as mediators of muscle atrophy and decay since their job is to cause degradation of protein." The first thing that this Velocigene approach allows you to do is validate these other techniques, which are purported to identify specific genes that are activated in atrophying muscles. The reporter knockins confirm the specificity of the muscle and their induction during atrophy.
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have discovered the key-signaling components, the potential drug targets for an important process that is detrimental in a variety of human conditions. We identified what we thought might be a key growth factor pathway that might mediate muscle growth, but how do you prove it?
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In knockout mice, the testes remain halfway up the body where they originally started because this GPCR is the peptide receptor that regulates gubernaculum contraction and descent of the testes. Once again, we got a totally unexpected potential therapeutic target.
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Because the receptor is so similar, it activates the same exact intracellular signaling pathways -- the STAT3 pathway that we initially characterized for the CNTF system. Axokine is really a leptin surrogate, but its big advantage is that it superactivates this brain region.
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No way to cause long-term, profound, and permanent weight loss. During treatment, we can get continuous weight loss while you are on the drug, but more importantly when you stop taking the drug, you maintain your weight loss due to Axokine.
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