Center of Biomedical Research Excellence in the Molecular Basis of Human Disease - VIRAL CORE

The overall objectives of the COBRE in the Molecular Basis of Human Disease at the University of Kentucky continue to be: (i) enhancing multidisciplinary research on the study of human disease, (ii) enhancing research competitiveness of the junior faculty who serve as principal investigators on research projects and pilot projects, and (iii) building and strengthening new core facilities to enhance the research capabilities of the principal investigators, their co-investigators, and researchers throughout the University. Significant progress has been made to achieve these objectives. This past year four COBRE PIs submitted research grants, with grant approval still pending. COBRE faculty published or have in press over 32 papers this past year and made 41 presentations at conferences and meetings. The core facilities supported by this COBRE grant continue to be broadly used by the COBRE faculty. The external advisory board met at the University in October of 2011 and heard presentations from each of the principal investigators and core directors. Following these meetings the external advisory board met with the PI Dr. Hersh and reviewed the progress of the projects and cores. This information was subsequently passed on to the junior faculty PIs, pilot grant PIs, and core directors. All projects were deemed to be progressing well. One of the projects has progressed to the point where funding for next year was considered unnecessary and another will be phased out receiving one more year of funding. In addition, a new faculty, Dr. Konstantin Korotkov joined the COBRE as a project PI. Dr. Korotkov's project is entitled "Structural biology of ESX secretion system from pathogenic mycobacteria." This project was reviewed at the External Advisory Committee Meeting and received favorable feedback. The COBRE mentors and PIs continued to meet on a monthly basis throughout the year. During this time the COBRE principal investigators and pilot project investigators made informal presentations, and discussed their projects, grant writing, publications, etc. These mentoring sessions continued to be very effective and useful for facilitating the research projects and for stimulating the junior faculty. The COBRE mentors began meeting on a quarterly basis as an advisory group to review progress of the PIs and to evaluate cores. We continued our training program on ethical and responsible conduct in research. All of the trainees involved in the grant participated and will continue to participate in this training program. This year two pilot awards were made to facilitate program project applications. The title of Dr. Donna Wilcock's pilot project is, "Investigating the roles of neuroinflammatory phenotypes in Alzheimer's disease using transgenic mouse models and AAV"; and Dr. Natalia Korotkova's project title is, "Function of Streptococcus pyogenes ADP-ribosyltransferase, SpyA, and a pheromone-like peptide, SpyB, associated with the enzyme." In addition through a supplemental NCRR ARRA grant a new core for the production of viruses for research was continued through a no-cost extension. In addition to our regular research project, we have two Planning grants, supported by funds awarded in the Administrative Core, with faculty who are working to generate preliminary data for a multi-PI or program project grant application. One of these headed by Dr. Trevor Creamer focuses on the molecular determinants of viral fusion protein transmembrane domain trimerization. This planning grant group consists of Drs. Trevor Creamer, Rebecca Dutch, Michael Fried and Craig Vander Kooi. The central goals of the project are to define motifs determining trimerization of the paramyxovirus fusion proteins and of the human T-lymphotropic virus 1 fusion protein. This planning grant will provide insight to the interactions leading to the trimerization of TM domains of viral fusion proteins from important human pathogens and hopefully lead to one or more new NIH grant submissions. The second planning grant headed by Dr. Douglas Andres aims to determine the molecular mechanism of Valproic Acid, a widely used anti-epileptic and mood-stabilizing drug. This planning grant group consists of Drs. Douglas Andres, Emilia Galperin, and Stefan Stamm. Preliminary studies have found that VPA abolishes the expression of the dicer protein, the central RNAse in the generation of miRNAs, resulting in the deregulation of a wide variety of miRNAs. Two specific aims are designed to test the central hypothesis that in addition to modulating gene expression by inhibiting histone deacetylases, Valproic Acid causes the loss of DICER protein, which changes the miRNA repertoire of the cell. Aim 1 will examine the mechanism and effect of Valproic Acid-mediated loss of Dicer protein. Aim 2 will explore downstream Valproic Acid signal transduction, and changes in alternative splicing alter membrane trafficking to increase insulin secretion. This work is significant as it helps define the mechanism of action of a frequently prescribed drug, including a novel mechanism involving long-lasting change in gene expression due to a change in the cellular processing of miRNAs. As with Dr. Creamer's planning grant we anticipate one or more grant proposals will develop from this group. Last year's planning grant led to several grant proposals included a funded NIH grant, indicating the succss of the planning grant program. The UK COBRE Web site is updated on a regular basis and can be accessed at: http://www.mc.uky.edu/biochemistry/cobre. This website appears to be an excellent venue for individuals to contact us, for disseminating information, and for communicating with faculty at this institution and elsewhere.