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

The overall objectives of the COBRE in the Molecular Basis of Human Disease at the University of Kentucky remain as: (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 our core facilities to enhance the research capabilities of the principal investigators, their co-investigators, and researchers throughout the University and region. Progress continues to be made in achieving these goals. This past year one new federal grant and two new non-federal grants were awarded to junior faculty supported by our COBRE. COBRE supported faculty published, or had in press, over 38 papers this past year and made 40 presentations at conferences and meetings. In addition two of our COBRE funded junior faculty were put up for tenure and promotion this year. The core facilities supported by this COBRE grant continued to enhance the research of the COBRE supported junior faculty with 105 faculty/post doc/staff, 73 graduate students, and 17 undergraduate students taking advantage of the COBRE core facilities. The one significant change regarding COBRE activities occurred with the Proteomics core supported by this COBRE. Plans were discussed to incorporate the Proteomics core into a broader Bioanalytical core. These plans are still under discussion, however at the end of the current funding period the Proteomics core will become a core fully supported by the institution. This reflects the positive impact the Proteomics Core has had on the institution and the institution’s commitment to this core. Similarly the ARRA supported Viral core became fully operational and was incorporated into the COBRE supported cores this year. This core continued to expand its services and was deemed a major success by users as well as the External Advisory Board. The Viral core expanded its teaching activities, by training a small number of students on viral techniques. The success of this endeavor will be expanded to have a group of the University’s Masters of Science students expand their expertise through training by the Viral Core. Studies conducted through the Organic synthesis core led to a patent application and the formation of a startup company. A second startup company based on compounds made by this core is being planned. The External Advisory Board held its annual met at the University in October of 2012 and heard presentations from each of the principal investigators and core directors. The External Advisory Board met in executive session 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 although the project of Dr. Wang was deemed to be lacking direction. Her project support will end at the end of the current fiscal year. The COBRE mentors and PIs continued to meet on a monthly basis throughout the year with the junior faculty COBRE principal investigators and pilot project investigators presenting their research followed by a discussion of the projects, and progress in grant writing, publications, etc. These mentoring sessions continue to be an effective and useful vehicle for facilitating the research projects of the junior faculty PIs and for stimulating faculty interactions. The COBRE mentors continued meeting with their mentees on a quarterly basis as an advisory group to review progress of the junior faculty PIs. The structure of these meetings were such that all aspects of the junior faculty member’s career were discussed. These meeting along with the monthly meetings described above provide maximum mentoring to the junior faculty. 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 six pilot awards were made. A project led by Dr. Craig Horbinski’s pilot project is, “Par-4 as a therapeutic target in gliomas.” The overall aim for this project is to identify how Par-4 is regulated by such alterations, and to begin studying ways of exploiting Par-4 to improve glioma therapy. As part of our research pilot grant program the COBRE, with funds from the administration and Department of Molecular and Cellular Biochemistry supported an additional five Planning grants. These pilot grants support groups of faculty working to generate preliminary data for multi-PI or program project grant applications. One of these headed by Dr. Stefan Stamm focuses on the DNA damage caused by aberrant pre-mRNA processing as a common cause for several human diseases. The central goals of the project are to determine how mutations in the protein fus are associated with amyotrophic lateral sclerosis. The project will test the hypothesis that changes in RNA processing result in alterations of chromatin modifications that destabilize the genome. A second planning grant headed by Dr. Michael Mendenhall aims are to bring low-cost Transcription Activator-Like Endonuclease (TALEN) and piggybac transposon mutagenesis technology to the UK campus. The former will permit site-specific manipulation of mammalian genomes while the latter will allow seamless excision of inserted maker sequences. The combination of the two technologies has been used to repair genetic defects in human cells and to create animal and tissue culture models of human genetic diseases. The third planning grant headed by Dr. David Rodgers is designed to develop an R01 application that focuses on investigating a proposed role of “cavities” or unfilled spaces in the enzyme choline acetyltransferase. These cavities are believed to be responsible for making choline acetyltransferase susceptible to a variety of apparently unrelated mutations that cause apnea and a number of related problems in patients carrying these mutations. Drs. Matthew Gentry and Craig Vander Kooi were awarded a planning grant that aims to determine the architecture and structure of malin, the physical and functional effects of disease-associated mutations, and the mechanism of malin function in glucan metabolism. A planning grant awarded to Dr. Sidney Whiteheart aims to elucidate the biological role of neuropilin in platelet function. The project will determine the contribution of neuropilin to platelet activation and endocytosis in an in vivo model. Last year’s pilot grants led to several grant proposals including an NIH R21, along with a manuscript currently under review indicating the success of this program. The UK COBRE Web site (http://www.uky.edu/cobre/) continues to updated on a regular basis including the notation of NIGMS funding. 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.