Susan Phillips - US grants

DESCRIPTION (provided by applicant): Obesity and diabetes are increasingly significant health care concerns. Type 2 diabetes (T2D), characterized by target tissue resistance to insulin and impaired pancreatic b-cell insulin secretion, affects 5-10% of the adult population. The amount of adipose tissue is highly correlated with and may contribute to insulin resistance. Obesity affects over 20% of the population and more than 80% of type 2 diabetics are obese, suggesting that obesity may be of pathophysiological importance to subjects genetically prone to develop diabetes. Multiple lines of evidence have suggested an endocrine role of adipose tissue to modulate energy homeostasis and insulin sensitivity, other studies suggest the possibility of a dynamic "cross-talk" relationship between muscle and fat. As skeletal muscle is the principal tissue of insulin mediated glucose disposal and the major site of peripheral insulin resistance in type 2 diabetics, these data give rise to the hypothesis that adipocyte endocrine dysfunction can result in glucose intolerance and insulin resistance in skeletal muscle. The long-term goal of this proposed study is to understand the communication between fat and muscle tissue in T2D. This study aims to determine 1) if fat from diabetic subjects contributes to the development of insulin resistance in skeletal muscle, and 2) if metabolic disturbances present in skeletal muscle from diabetic subjects alters the metabolic behavior of adipose tissue. Specifically we will use adipose and skeletal muscle biopsy tissue and cultured cells from diabetic and control subjects to ask: 1) what is the metabolic behavior of isolated adipocytes or myocytes in culture and how is it altered when their physiologic proximity is restored in culture? 2) What is the effect of T2D on the metabolic behavior of these tissues and is fat-muscle communication altered when proximity is re-established in culture? 3) Can treatment of either tissue alone with anti-diabetic thiazolidinediones alter the nature of the communication between these tissues when their physiologic relationship is restored in culture? Studying fat-muscle communication will enhance our understanding of the molecular mechanisms underlying obesity-diabetes syndromes, and may suggest new treatment strategies.

DESCRIPTION (provided by applicant): The short-term goal of this R21 Translational Research Grant PAR 06-095 application, entitled "Noise-induced hearing loss: threshold, exposure, and genetic susceptibility," is to establish a basis for identifying people showing a genetic susceptibility to noise-induced hearing loss (NIHL). The application is proposed by a team of three researchers: The PI is Susan L. Phillips, Ph.D. in audiology (CCC-A), who is working with Co-PI's Vincent C. Henrich, Ph.D. in genetics, Scott J. Richter, Ph.D. in statistics and Sandra T. Mace, Ph.D. in music education and certified Hearing Conservation Specialist. It is known that acoustic overexposure can cause noise-induced hearing loss. Nevertheless, there is considerable variability in NIHL even among subjects who have not experienced unusual levels of acoustic exposure, and, thus, there is a critical gap in our knowledge about who is and is not most at risk for NIHL. This project will fill the gap in knowledge by identifying the critical variables associated with a genetic predisposition to NIHL. Critical variables identified in our study so far include the audiological profile (unilateral or bilateral, depth of notch and frequency of notch), reported current and past acoustic exposure and measured acoustic exposure (intensity and duration). The Specific Aims are: 1) Compare the crude and adjusted prevalence among subjects with bilateral, unilateral, or no notches of variants at several gene loci found in previous research to be associated with NIHL. Based on criteria laid out in Phillips et al. (in press), the working hypothesis will be that the frequency of predisposing alleles for NIHL will be higher among individuals with bilateral notches than in those with unilateral or no notches. 2) Examine whether there are significant gene-environment interactions present. The working hypothesis will be that the individuals with the highest current exposure and carrying predisposing alleles to NIHL will show the greatest progression of NIHL. We will make direct and indirect measurements of thresholds and exposure levels in a study involving 1,000 students between the ages of 18-25 years, allowing us to avoid the confounds present in other genetic association studies of NIHL. These include age-related hearing loss and disease factors that can contribute to hearing loss, additional chemical exposures that can contribute to hearing loss, and the extreme exposures and exposure durations associated with industrial populations. Previous studies have found it necessary to apply statistical corrections for these confounds and the corrections were acknowledged to have complicated the interpretation of the data (Konings et al., 2009). Buccal cells will be collected and DNA extracted from students in three groups: those with bilateral notches, with unilateral notches, and a control group of students with no notches. The project's relevance to public health is reflected in our long-term goal, which is to use a mechanistic understanding of NIHL to develop a personalized NIHL prevention program using standard clinical audiological tests as indicators of genetic susceptibility. The ability to identify at-risk individuals and exposure situations at an early age, perhaps through the development of a NIHL Risk Profile, will allow health care providers, music educators, industrial and military hearing conservationists, and others to target preventive measures to at-risk individuals. Preventive measures include education, the use of hearing protection devices, sound attenuation modifications to exposure sites and monitoring of exposure intensities and durations. PUBLIC HEALTH RELEVANCE: NIHL is a growing health concern among children, found in 15.5% aged 12-19 (Niskar et al., 2001), in 28% of college students who listen to personal listening devices (Mostafpour et al., 1998), and 44% of student musicians in a university School of Music (Phillips et al., in press). The short-term goal of this application for an R21 Translational Research Grant PAR 06-095, entitled "Noise-induced hearing loss: threshold, exposure, and genetic susceptibility," is to establish a basis for identifying people showing a genetic susceptibility to noise-induced hearing loss. The relevance of the project to public health is reflected in the long-term goal, which is to use a mechanistic understanding of noise-induced hearing loss to develop a personalized prevention program using standard clinical audiological tests as indicators of genetic susceptibility.