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Professional Interests - Publications - Contact Information - Lab Personnel Professional Interests of Lewis Jacobson
Dr. Jacobson's laboratory is interested in the physiological and hormonal factors that control the degradation of proteins in muscle. Abnormally rapid muscle protein degradation is associated with various disease states that lead to muscle wasting or muscle atrophy, including cancer, sepsis, AIDS, renal failure, diabetes and chronic inactivity. The soil nematode Caenorhabditis elegans is used as a model organism for these studies, because of the exceptional convenience of genetic manipulation and analysis and the overall cellular simplicity of the animal. Over the past few years, our work has shown that muscle protein degradation is regulated by diverse networked signal-transduction pathways that control several different proteolytic systems (see Figure below). This level of complexity was unanticipated and poses a variety of challenges to our understanding of how these crucial processes are regulated.
In a 2007 paper in EMBO J., the Jacobson lab has shown that mutational or drug inhibition of signaling in the IGFR-PI3K-PDK-Akt pathway promotes muscle protein degradation. Temperature upshift of daf-2ts (IGFR) or age-1ts (PI3K) mutants or drug inhibition of PI3K provokes protein degradation (see blue stain of muscle reporter protein in Figure below) by releasing inhibition of the FGFR-Ras-MAPK signaling pathway.
One surprising implication of these studies is that Ras signaling is normally "on" in muscle in response to autocrine FGF signal, but its effect is suppressed at the level of Raf by signal from the IGFR pathway, which is also normally "on". Thus, in normal muscle two signaling pathways balance each other to prevent muscle protein degradation. These findings suggest a new view of how signaling occurs to provoke protein degradation: Rather than proteolysis being triggered when a single signal is turned from "off" to "on", what is important is the balance between two or more sets of signals with opposing effects. We believe this makes sense from a physiological viewpoint, in that muscle must monitor a variety of physiological variables and enter the state of protein catabolism when "unfavorable" signals are too high or "favorable" signals are too low. Current work in the lab focuses on how muscle protein degradation is regulated by (a) TGF-beta signaling; (b) serotonin (5HT) signaling; (c) intramuscular calcium and various muscle calcium channels; (d) calcium-activated protein kinases. These efforts are greatly facilitated by our unique collection of over 280 mutant strains with altered signaling. Spacefaring worms: We are also continuing to develop C. elegans as a model to study muscle atrophy in the microgravity environment of the Space Shuttle and the International Space Station. Loss of muscle mass and strength is one of the most serious biomedical obstacles to long-term human activity in space. Since many of the signals that regulate protein degradation in the muscles of C. elegans also operate in analogous ways in human muscle, we hope that our studies will show the way to physiological and/or pharmacological remediation of muscle atrophy induced by the microgravity environment as well as by disease processes. The lab environment: The lab has long been known as "The Zoo" for its informal atmosphere and traditional dedication to Marxism (Groucho, not Karl). We are usually a diverse and age-heterogeneous group, ranging from beginning undergraduates to postdocs. Publication
Archive Recent Publications of Lewis Jacobson
Jen-Jacobson, L., and L.A. Jacobson (2008) The role of water and the effects of small ions in site-specific protein-DNA interactions. Pp in Structural Biology of Protein-Nucleic Acid Interactions, Rice, P.A., and C. Correll, Ed. Royal Society of Chemistry Publishing, Cambridge, UK
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