Co-Funded Research

Principal Investigator: Marinella Temprosa

Institution: George Washington University

Grant No.: 2U01DK048489

Award: $400,000

Abnormal regulation of glycemia ("dysglycemia") has a very long time course, from its earliest stage, labeled pre-diabetes, to the onset of Type 2 diabetes (T2D), to the development of clinically detectable microvascular changes and measurable atherosclerosis, to clinically manifest complications with attendant morbidity and mortality. The Diabetes Prevention Program (DPP) focused on the pre-diabetes stage of dysglycemia and demonstrated powerful beneficial effects of lifestyle intervention (ILS) and metformin (MET), compared with placebo (PLBO), in preventing or delaying the onset of T2D over a 3-year period in a high-risk population (n=3234). The DPP also investigated and described the interventions, phenotypic and genotypic risk factors associated with T2D development, the effects of the interventions in the setting of these risk factors, the health economic implications of T2D prevention, and other outcomes of interest. Based on these results, the DPP lifestyle program has been widely implemented. The 11-year follow-up DPP Outcomes Study (DPPOS) explored the longer-term effects of T2D prevention, bridging the period between pre-diabetes and T2D, and examined outcomes that required more time to develop than the relatively brief 3-years of DPP. DPPOS showed longer- term salutary effects of the original interventions on T2D prevention and on cardiovascular disease (CVD) risk factors. Prevention was cost-saving with MET and cost-effective with ILS. Overall, the risk for microvascular disease was significantly greater in subjects who developed T2D and increased with longer duration and higher hemoglobin A1c (A1C). There were no significant differences by treatment group in the prevalence of the aggregate microvascular outcome; however, compared with PLBO and MET, ILS significantly reduced the risk of microvascular disease among women and those who had A1C ≥6.5% at study end. The proposed DPPOS Phase 3 will study the DPPOS cohort for 10 more years, taking advantage of the long- term randomized exposure to MET and the densely phenotyped and genotyped DPPOS cohort (n=2778), which includes nearly 1600 patients with known T2D duration and ~1200 who have not developed T2D, to address yet unanswered questions about long-term exposure to MET and ILS initiated during pre-diabetes. DPPOS Phase 3 will examine outcomes that are of increasing public health concern in the aging population with pre- diabetes and T2D, including the putative benefits of MET on development of CVD and cancer. The main goals of DPPOS Phase 3 are to examine efficiently: 1) the long-term effects of metformin therapy begun in the pre- diabetic phase on risk for CVD and cancer; 2) the long-term effects by intention-to-treat of ILS and MET on further development of T2D and on traditional and more recently recognized complications of dysglycemia, and of their economic impact; and 3) the clinical course of dysglycemia, evaluated by categorical diagnoses (pre-diabetes vs diabetes) and as a continuum, and their associations with the development of complications, including analyses of interactions with DPP interventions and established and novel risk factors.

Principal Investigator: Gregory Allen Buck

Institution: Virginia Commonwealth University

Grant No.: 3U54HD080784

Award: $500,000

In the U.S., the annual cost of health care for newborns with complications approaches $26 billion, and worldwide, preterm birth is the leading cause of morbidity and mortality among neonates. Despite improved survival rates, the past few decades have seen no significant decrease in preterm births. It is becoming clearer that the billions of bacteria that colonize the human body play important roles in the health of the individual. However, the role of the millions of bacteria and other microbes that colonize the human female urogenital tract in prenatal health and birth of a healthy baby remains obscure. Previous to the recent development of 'omics' technologies; i.e., genomics, transcriptomics, proteomics, metabolomics, interactomics, etc., it was not possible to study these microbial populations in any in depth or highly efficient way. Many of these organisms have never been characterized and a fairly large fraction have not been successfully cultured. Herein, we propose to use these 'omic' technologies to dissect the bacterial populations that inhabit and colonize the female urogenital tract of pregnant women to assess the role(s) of these organisms in maintenance of health or in the cause of disease in these women and their babies. An understanding of the roles these organisms play in the health of the female urogenital tract will lead to better, more efficient prenatal and postnatal care, likely leading to diminished levels of preterm birth and infant morbidity and mortality.

Principal Investigator: Samuel A. McLean

Institution: University of North Carolina at Chapel Hill

Grant No.: 5R01AR064700

Award: $75,000

Each year, more than 100,000 U.S. women seek emergency medical care after sexual assault (SA). Most women do not return for/receive further care related to SA after initial emergency evaluation. Thus the emergency care visit represents a unique opportunity to identify SA survivors for preventive interventions to improve recovery. Cross-sectional studies indicate that chronic musculoskeletal pain (MSP) is reported by many SA survivors and is associated with substantial suffering and poor health outcomes. However, no prospective studies evaluating chronic MSP outcomes after SA have been performed, and therefore a firm etiologic link between SA and chronic MSP has not been established. In a recent prospective pilot study (n = 83), the investigators found that 41% of women SA survivors enrolled developed chronic moderate or severe MSP. Initial pain scores collected from all women approached for pilot study participation showed that more than half of those at high risk of chronic MSP consented and enrolled in the pilot study. In addition, data collected indicate that women SA survivors who participated in the pilot study are the same group of SA survivors who would be willing to participate in preventive intervention trials. However, currently no information exists regarding key factors that influence the transition from acute to chronic post-SA MSP to inform the design of such trials. Available evidence suggests that posttraumatic stress disorder (PTSD) symptoms may be key factors mediating the transition from acute to chronic post-SA MSP. PTSD symptom clusters have been found to mediate the transition from acute to chronic MSP in other trauma populations, and the investigator's pilot data support these relationships in the study population. Importantly, despite evidence that PTSD symptoms are key factors mediating chronic post-SA MSP development, available data also indicate that not all individuals with acute MSP develop PTSD symptoms, and not all individuals with PTSD symptoms develop chronic MSP. This suggests that important individual differences moderate these relationships. Available evidence, and the investigator's pilot data, suggests that genetic variants affecting the function of hypothalamic-pituitary-adrenal (HPA) and catecholaminergic systems constitute such important individual differences. The investigators propose a prospective cohort study of women SA survivors (n = 900) evaluated 1 week, 6 weeks, 6 months, and 12 months after SA. A methodological approach including Confirmatory Factor Analyses and Structural Equation Modeling will be used to test the hypotheses that chronic MSP is common in the study population, that PTSD symptom clusters mediate the relationship between acute and chronic MSP after SA, and that the proposed genetic factors moderate these relationships. Results of this groundbreaking study will generalize to a large population of women SA survivors who experience a high burden of chronic post-SA MSP, and will inform the development of preventive interventions for this understudied population.

Principal Investigator: Patrick O. Kanold

Institution: University of Maryland, College Park

Grant No.: 5U01NS090569

Award: $250,000

The cortex is a laminated structure that is thought to underlie sequential information processing. Sensory input enters layer 4 (L4) from which activity quickly spreads to superficial layers 2/3 (L2/3) and deep layers 5/6 (L5/6) and other cortical areas eventually leading to appropriate motor responses. Sensory responses themselves depend on ongoing, i.e. spontaneous cortical activity, usually in the form of reverberating activit from within or distant cortical regions, as well as the state and behavioral context of the animal. Receptive field properties of neurons can rapidly and adaptively be reshaped when an animal is engaged in a behavioral task, indicating that encoding of stimuli is dependent on task- or context-dependent state. Responses also depend on ongoing cortical dynamics in a lamina-dependent fashion and differ between the awake and anesthetized state. The intricate neuronal interplay between behavioral context, ongoing activity, and sensory stimulus underlying cortical representations is unknown. Specifically, we do not know how neuronal circuits shape these emergent dynamics within and between laminae, and we do not know which neurons encode which aspect of a sensory stimulus. One shortcoming of all prior studies of sensory processing is that only a few neurons are sampled, and thus information about the interactions between neurons, and between neuron and global brain state is lacking. Here we address these challenges by developing new in vivo 2-photon imaging technology that allows rapid imaging and stimulation in multiple focal planes and new computational and information theoretic techniques to extract network dynamics at the single neuron and population level. These measures go beyond paired measures and take synergistic interactions between neurons into account. We use these new techniques to investigate the 3D single cell and population activity patterns in the auditory cortex in mice. We investigate the influence of single neurons relative to the synergistic influence of specific groups of neurons (the crowd) on network dynamics and ultimately behavior of the animal.