Chronic stress is a factor in many psychiatric diseases, such as depression, PTSD and other anxiety disorders. The brain noradrenergic (NE) system is important in arousal and acute stress reactivity, and is implicated in the etiology of stress-related psychiatric disorders. In the previus grant period, we showed that increasing NE transmission acutely in the prefrontal cortex (PFC) of rats facilitates cognitive flexibility on an attentional setshifting test (AST). By contrast, chonic unpredictable stress (CUS) compromised cognitive flexibility.

Major manifestations of diabetic nephropathy are increased enal hypertrophy involving glomeruli and tubules with expansion of matrix proteins, including fibronectin. These changes occur concomitant with increased expression of transforming growth factor-ø?(TGFø) that contributes to the pathogenesis of human and experimental diabetic nephropathy. The mechanisms by which hyperglycemia and/or TGFø ?result in hypertrophy and increased expression of fibronectin are poorly understood.

3-aminobutyric acid, or GABA, is the main inhibitory neurotransmitter in the mammalian brain. Dysfunctions in GABA-mediated inhibition have been implicated in the etiology of a variety of brain disorders. Furthermore, GABA receptors are targets for a host of therapeutic and endogenous modulators such as benzodiazepines, barbiturates, and neurosteroids. Key to understanding the etiology of these diseases and the molecular mechanisms of these modulators, is a detailed understanding of the activation mechanism of the GABA receptor.

Opioid receptor agonists remain the drugs of choice to treat moderate to severe pain, but their use is limited by adverse effects including tolerance, dependence, abuse, and respiratory depression. A recent increase in overdoses and deaths is fueling concerns about opioids that further limit their legitimate medical use. A growing body of evidence indicates that the therapeutic window of an opioid can be increased by combining it with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect.

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.

This proposal defines a multi-disciplinary postdoctoral research training program to annually support six graduates of medicine, veterinary medicine, or the basic biomedical sciences. The past 29 years of this program document an impressive record of successfully training young scientists; indeed, 87% of completed trainees in the past decade (n=22) remain in research or training, and 10 received independent funding while supported by this program.

Tubulointerstitial fibrosis is a prominent pathological feature of progressive renal disease including diabetic nephropathy. In diabetic nephropathy and other progressive renal diseases, tubular epithelial cells acquire mesenchymal cell characteristics and accumulate matrix proteins that eventuate in fibrosis. Two potential mediators of renal fibrosis in diabetes are high glucose concentrations and transforming growth factor-beta.

Basic Research

Basic Research

Basic Research