Christopher King - US grants

This Engineering Faculty Internship is a collaborative effort between the University and an industrial partner. It will result in a computer system that will provide human-machine integration within the production environment. The system, will use standard statistical process control methods for quality assurance plus Bayesian Analysis and will integrate the entire manufacturing facility under a user-friendly, multi-user, custom-made, data- base. This project has the potential to greatly enhance the quality assurance effort of the corporation. //

DESCRIPTION (provided by applicant): In 2003, a complete draft of the entire human genome was completed. Currently, efforts are underway to extend this sequencing project to larger number of individuals, some of whom are part of studies looking for links between genetic variation and health outcomes. Other projects will sequence only small parts of the genome which are suspected to be the most relevant to diseases. Association studies like these are of importance to NHLBI because they are able to more directly identify causative mutations and genes than previous kinds of genetic association. These studies will run into difficulties with statistical analysis of their results. This fellowship will train the candidate in development of novel techniques to increase the utility of advances in underlying tech- neology for understanding disease. Current methods test each mutant (single nucleotide polymorphism - SNP) for a disproportionate frequency in diseased and normal participants. However, several features of sequence data will make such comparisons uninformative. First, there are a huge number of SNPs which can be detected, around twenty million to date;the multiple testing problems with this many SNPs means that only the strongest associations are detectable. Second, functional SNPs (those changing the protein makeup) come in several varieties, and non-functional SNPs have many potential relationships to the nearby gene. Current methods treat these varieties as equivalent, which ignores some potentially important information. Third, these methods do not take advantage of the clustering of relevant variants near each other. Once you have identified a SNP as being associated with disease, other SNPs in the same gene should be considered more likely than before to be relevant. Fourth, many of the SNPs identified by sequencing will be rare. If a SNP only appears in a few people in a study, the evidence for or against it being important will be weak, and the study will not be able to reach conclusions about most of the variation it detects. We will develop new analysis methods which address these problems. Our methods will use predefined collections of SNPs within and nearby protein coding regions and conserved non-coding regions to look for patterns of association, taking into account the local correlation, SNP frequencies, and predicted SNP type. Testing and perfecting the method on whole genome sequencing will be done with simulation and the initial draft of the 1000 Genomes Project and drug-response phenotypes. Second, we will demonstrate our techniques for candidate gene confirmation using resequencing of 9 genes previously implicated in asthma in 500 normal individuals and 500 asthmatics. 1 PUBLIC HEALTH RELEVANCE: This project will give genetic resequencing projects additional power to detect disease causing mutations. Locating disease causing mutations will allow the creation of effective screening tests and suggest targets for new therapies for common diseases such as asthma.

DESCRIPTION (provided by applicant): Improving Animal Resources at the University of Georgia The University of Georgia (UGA) is a large research-intensive, land-grant university with historic strengths in the agricultural and environmental sciences. For over a decade, UGA has prioritized the expansion and strengthening of its biomedical and health-related programs, and this has in turn produced a dramatic growth in the use of laboratory rodents, particularly mice. This growth has occurred at the same time we have moved to consolidate and upgrade laboratory rodent care in the modern and efficient vivarium housed in the new Paul D. Coverdell Center for Biomedical & Health Sciences. The Coverdell Rodent Vivarium (CRV) is a large state-of-the-art barrier facility that if properly equipped can replace aged, dispersed and haphazardly equipped conventional facilities to become the flagship home for laboratory rodents in UGA's AAALAC-accredited animal care and use program. Sizeable investments by UGA in recent years have enabled considerable progress towards the equipping of the CRV but recent fiscal austerity has prevented full utilization of the facility and also impaired efforts to keep pace with equipment needs for near term and projected research growth. The specific aim is to provide individually ventilated rodent caging (IVC) systems, biosafety cabinets and ventilated change stations to enhance and extend the capabilities of the Coverdell Rodent Vivarium (CRV) to meet research needs. Despite successive investments in new IVC systems, housing now available in the CRV is sufficient only to meet current needs, with no additional capacity available for new grants already approved for funding or for new programmatic growth resulting from planned new faculty hires. The strain has been exacerbated by the need to downsize or close a number of outdated and inefficient rodent facilities, and to largely consolidate rodent care in the modern efficient Coverdell Rodent Vivarium, which now houses over 80% of the campus rodent census. The equipment requested in this proposal will allow us to meet foreseeable future growth in the use of laboratory rodent models as the biomedical sciences at UGA continue to expand. We project that the CRV mouse census will grow by 41% during the next year. The requested equipment will provide 37% additional capacity. The improvements proposed will directly affect $12.7 million in active NIH funding and $20.9 million in funding from all other sources, both federal and non-federal. UGA's total funding for animal-based research reached $29.8 million in FY2010, increasing over 100% from just four years ago. Funding for 14 additional Tecniplast Sealsafe IVC racks and caging is being sought to provide an additional 1840 cages or 37% of additional capacity. Funding for 4 additional 4' Class IIA2 BSCs and 5 additional ventilated change stations is requested to enhance animal holding capabilities. The total cost of the equipment is $670,880. A total of $500,000 is requested with UGA providing a 34% match of $170,880.

DESCRIPTION (provided by applicant): The primary goal of this Career Development Award (K99/R00) is to provide protected time for the candidate to obtain the necessary training and mentoring to establish an independent clinical research program for understanding physiological and psychological mechanisms underlying pain modulation and how these mechanisms contribute to Temporomandibular Joint Disorder (TMJD). The current proposal extends the candidate's previous background in stress and pain psychophysics with additional training to investigate physiological and psychological factors involved in the pathophysiology of TMJD. Specific training areas in the mentored phase of the K99 will help the candidate achieve several short-term goals including developing expertise in psychoneuroimmunology (PNI), psychological theory and assessment, and clinical exposure through guided mentorship, didactic coursework, and applied research experiences in healthy controls (HC) and in patients with TMJD. In addition, the training will establish the candidate as an independent clinical researcher by increasing his productivity, which will assist in obtaining a tenure-track faculty position and independent funding. Long term goals of the training include establishing an independent research laboratory to investigate physiological and psychological factors mediating clinical and experimental pain. The mentored phase of the K99 will take place at the University of Florida College of Dentistry under the direct mentorship of Dr. Roger Fillingim, Ph.D. and co-mentorship of Dr. Joseph Riley, Ph.D., both mentors are nationally and internationally respected experts in the field of pain and orofacial research. The environment is ideal for this project because the university places a strong emphasis on pain research including orofacial pain. The necessary laboratory, equipment, and supplies needed to complete the series of studies described in this proposal are available to the candidate. The research plan offers a series of studies that are designed to elucidate factors mediating the reduced efficacy of endogenous pain inhibition TMJD patients based on a model of conditioned pain modulation (CPM). In this model, pain inhibition is characterized by a reduction of heat pain sensitivity during exposure to a tonic conditioning stimulus. While the mechanisms remain unknown, the reduced pain inhibitory capacity in TMJD could be due to a maladaptive stress system, which is influenced by abnormal physiological (i.e., endogenous opioids, cholecystokinin) and psychological (i.e., catastrophizing) responses to pain. The research plan will use the skills developed during the career plan to investigate the impact of maladaptive neuroendocrine and pro-inflammatory immune responses and negative psychological reactions as important factors in reduced pain inhibition in TMJD. These observations will be accomplished by cross-sectional evaluations (Aim 1) and experimental manipulations of pain expectation (Aim 2). The candidate will use the skills and knowledge gained during the mentored training phase (K99) to transition to the independent (R00) phase. Aim 3 will investigate the interactions of endogenous opioid and cholecystokinin systems with psychological and biological responses to pain. The proposed series of studies will provide a more thorough understanding of endogenous pain modulation in patients who suffer with TMJD. Since it is the goal of the National Institute of Dental and Craniofacial Research (NIDCR) to understand the causes of orofacial pain, the mechanisms underlying endogenous pain inhibition are a potential target that could assist in development of therapies to prevent and treat TMJD. PUBLIC HEALTH RELEVANCE: As a public health problem, TMJD is the most common chronic orofacial pain condition, associated with an overall negative impact on quality of life and a burden to our health care system. Current evidence regarding causes of TMJD is beginning to emerge, but additional research is needed. The current proposal addresses goals within the NIDCR strategic plan, which calls for studies that identify the causes and effects of orofacial pain, by enhancing our understanding of the mechanisms contributing to an imbalance in pain processing and modulation in TMJD patients.