Pain affects more Americans than does diabetes, heart disease and cancer combined. Opioids are a key drug class for pain treatment; however, there are significant drawbacks (e.g. CNS adverse effects, social and legal issues) that limit their use for effective management of pain. Consequently, development of novel approaches for improved pain control is a critically important research objective. To eliminate adverse CNS-derived effects, attention has turned to targeting peripherally located opioid receptors expressed on the pain-sensing neurons themselves.

Burns often lead to persistent pain not well managed by available analgesics. The mechanisms of burn pain are incompletely understood. However, the TRPV1 (transient receptor potential V1) receptor appears to be pivotally involved in post-burn pain. In our preliminary data, ~67% of post-burn thermal hyperalgesia is blocked by peripheral injection of a TRPV1 receptor antagonist. In addition, extracts of burned human skin produce thermal hyperalgesia when injected into rats via a TRPV1 receptor mechanism.

Diabetic retinopathy (DR), a complication of diabetes and the leading cause of blindness in working-age adults, is a retinal disease whose prolonged course typically begins years prior to diagnosis. DR is presently diagnosed by clinical findings on examination; by the time these are visible, significant irreversible damage to the retina has already occurred for most patients. Insufficient oxygen delivery and hypoxia associated with the energy-demanding photoreceptors has been implicated in the early stage of the disease.

Cognitive flexibility is the ability to modify pre-established behaviors, habits, learned contingencies and patterns of thought based on new information from a changing environment. This ability is significantly impaired in several psychiatric disorders that include psychosis, neurodevelopmental, and affective disorders. Cognitive dysfunction is not only an important contributor to chronicity and recurrence of symptoms; it is also a predictor of poor treatment outcome, and the cognitive impairment itself is often resistant to improvement by pharmacological or other interventions.

Bone loss and fracture are leading causes of morbidity with aging. The mechanisms of age-related bone disease have not been defined. Our studies suggest that CSF-1 deficiency and increased Nox4 oxidase expression in osteocytes are key determinants of oxidant stress that impact osteocyte survival/function that is essential for bone remodeling. The long-term goal of this proposal is to delineate mechanistic pathways by which CSF-1/oxidative stress regulate osteocyte homeostasis and identify therapeutic targets to prevent bone loss with age. CSF-1 and CSF-1R are expressed by osteocytes.

Type 2 Diabetes (T2DM) is the seventh leading cause of death in the United States, and is quickly becoming a global pandemic. Its patients suffer either reduced insulin production or insulin sensitivity, the latter of which has been associated with reduced nitric oxide synthase (NOS) activity in T2DM skeletal muscle. NOS proteins produce the gaseous signaling molecule nitric oxide (NO), which has been implicated in glucose uptake and insulin sensitivity. In skeletal muscle, NO is produced by neuronal nitric oxide synthase (nNOS), the tissue's primary NOS isoform.

An adverse intrauterine environment, seen in pregnancies complicated by preeclampsia, obesity or intrauterine growth restriction (IUGR), programs the offspring for disease in later life. Placental function regulates fetal growth and development, transducing the maternal and uterine environment to the fetus, and mediating fetal programming. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through translational repression or mRNA degradation.

With a high attributable mortality rate of 40-50%, Candida species represent the fourth leading cause of hospital-acquired bloodstream infections in the United States. These fungal pathogens are normally found as commensals in mammalian mucosal niches, especially the oral cavity. In immunocompromised patients, Candida overgrowth leads to the formation of biofilms, which play an important role in the development of infection. Biofilms are complex microbial communities that adhere to a surface and are enclosed within an extracellular matrix.

Adipose tissues play key roles in the storage, release, and dispersal of highly energetic molecules to maintain energy homeostasis of the organism in response to environmental and hormonal stimuli. Adipose tissue dysfunction is associated with obesity and various metabolic diseases.

In order to develop a novel restorative system with at least twice the lifetime of Bis-GMA/TEGDMA- based composites, their incomplete cure and susceptibility to hydrolysis and esterase degradation must be overcome. To address these problems, we will develop a novel superhydrophobic, degradation-resistant, dental restorative based on an Oxirane/Acrylate interpenetrating network System (OASys, pronounced Oasis).