Homeostatic mechanisms function to maintain a narrow range of blood glucose levels in response to hormones released within the body as well as nutrients ingested. However, these tightly regulated mechanisms can become dysregulated through a variety of factors. For example, high stress and intense exercise conditions combined with food deprivation make soldiers very vulnerable to changes in blood glucose levels. Additionally, glucose homeostasis is highly dysregulated in metabolic diseases, such as obesity and diabetes, which are on the rise in many populations. Due to the widespread, negative impact of glucose homeostasis dysregulation, Dr. Puigserver, using a 2005 Peer Reviewed Medical Research Program Investigator-Initiated Research Award, proposed to study a biochemical process that controls blood glucose levels through the control of hepatic glucose synthesis. Specifically, Dr. Puigserver wished to decipher how two proteins, CCDC101 and WDR18, regulate the key metabolic transcriptional coactivator PGC-1a. Research results have demonstrated that CCDC101 and WDR18 are part of the PGC-1a transcriptional complex. Furthermore, he found that WDR18 indirectly regulates PGC-1a activation. Although WDR18 is required for the maximum transcriptional activity and expression of gluconeogenic genes (which leads to increased blood glucose levels), the expression of hepatic glycolytic genes, which leads to decreased blood glucose levels, is not affected by expression of WDR18. However, expression of a PGC-1a mutant that is not sensitive to nutrient-dependent activation demonstrated an overexpression of gluconeogenesis and glycolytic genes, supporting the hypothesis that PGC-1a activation is the key to controlling glucose and lipid metabolism. Dr. Puigserver continues his research, hoping to identify therapeutical targets that can be used to prevent glucose and lipid dysregulation.
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Coste A, Louet JF, Lagouge M, et al. 2008. The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1alpha. Proc Natl Acad Sci USA 105(44):17187-17192.
Rodgers JT, Lerin C, Gerhart-Hines Z, et al. 2008. Metabolic adaptations through PGC-1alpha and SIRT1 Pathways. FEBS Letters 582:46-53.
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The physiologic response to severe injury from chemical or physical sources can be very complex, creating a challenge to the medical community from the perspective of treatment, survival, and recovery. The biological events associated with wound healing in general include inflammatory, proliferative, and remodeling phases. As part of this complex series of cascading events, inflammation in wound healing is an outcome of the immune response as the body attempts to cleanse the wound of microorganisms and necrotic debris. The body then begins to rapidly rebuild the epithelial (skin) structures, typically resulting in scar tissue. Drs. R. Daniel Little and Robert S. Jacobs, and their students at the University of California at Santa Barbara are exploring the utility of natural compounds found in the ocean environment to assist the wound healing process and mitigate the body's tendency to construct scar tissue.
Dr. Little received a Fiscal Year 2005 Existing Program Project Award through the Peer Reviewed Medical Research Program to examine the potential use of the pseudopterosins, a class of compounds found in sea fans and sea whips and their analogs, in wound healing. Specifically, Dr. Little's research aims to design and synthesize chemically simplified substances (called the minimal pharmacophore) mimicking the natural pseudopterosins anti-inflammatory properties. The synthetic compounds produced in Dr. Little's laboratory include modifications to the natural products at specific sites suspected to play an essential role in wound healing in an effort to improve the compound's efficacy. Since project inception, Dr. Little and his team have established methods to structurally modify the natural pseudopterosin framework and synthesized a wide variety of simplified chemical analogs. In addition, they have discovered a new member of the pseudopterosin class of marine natural products, an isomer of a known pseudopterosin, which has been named iso-PsE. Compounds created by Dr. Little's team are evaluated by a group headed by Dr. Robert S. Jacobs in assays designed to determine the agent's biological activity and assess potential to augment the wound healing process. Future studies of these compounds include in vivo evaluations of the wound healing properties of identified agents in animal models.
This research is paramount to identifying naturally available anti-inflammatory substances that may be synthetically produced and enhanced to promote effective wound healing. Abetting wound healing is a very important issue for the warfighter as well as the general public.
Photo used with permission of Valerie J. Paul
Hoarau C, Day D, Moya C, et al. 2008. iso-PsE: A new pseudopterosin. Tetrahedron Letters 49(31):4604-4606.
Tanis VM, Moya C, Jacobs RS, et al. 2008. Synthesis and evaluation of the bioactivity of simplified analogs of the seco-pseudopterosins; progress toward determining a pharmacophore. Tetrahedron 64(47):10649-10663.
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Wound infection, whether in trauma wounds, surgical sites, or chronic wounds, is a serious problem in both military and civilian life. Inappropriate antibiotic use may contribute to the development of resistant bacterial strains. The ability to select the appropriate antibiotic for treatment depends on correctly identifying the bacterial pathogen(s) in the wound.
Dr. Sydney Finegold of the Veterans Affairs Medical Center of West Los Angeles, recipient of a Fiscal Year 2004 Peer Reviewed Medical Research Program Investigator-Initiated Research Award, developed a strategy that speeds up the pathogen identification process by using direct detection of characteristic bacterial genes in clinical specimens. Traditionally, bacterial identification has been through isolation of each bacterial species into a pure culture that can be identified phenotypically by a set of biochemical tests such as might be done to determine whether bacteria have caused a throat infection. However, some wound pathogens are slow-growing, otherwise difficult to grow, or even impossible to grow in pure culture. Without timely and proper wound pathogen identification, patients may receive an inappropriate or unnecessary broad-spectrum antibiotic. By using PCR technology to probe for DNA sequences unique to bacterial pathogens, Dr. Finegold's method is bringing speed and accuracy to pathogen detection. In an analysis of 400 surgical and wound infection clinical specimens, 91% of the pathogens were identified to the genus or species level 1 to 3 days faster than using conventional phenotypic tests. Additionally, this method allowed for identification of new pathogens including a novel anaerobic, non-spore-forming, Gram-negative bacillus that, based on the morphological and biochemical criteria, was placed in the genus Porphyromonas.