Gastroparesis is a common complication of diabetes and can involve pathogenic oxidative stress. In rodent models, reduced nitric oxide (NO) bioavailability as a result of neuronal nitric oxide synthase (nNOS) uncoupling and increased reactive oxygen species (ROS) has been shown to play a role in delayed gastric emptying. The transcription factor nuclear factor (erythroid-derived-2)-like 2 (NRF2) regulates the expression of Phase II antioxidant and detoxification genes. Preliminary studies in rodent model of diabetes showed that the expression of NRF2 and its target genes, Gclc and Gclm, is suppressed while oxidative stress is elevated. We have demonstrated that loss of NRF2 (Nfe2/2-/-) resulted in decreased levels of tetrahydrobiopterin (BH4, a critical cofactor for nNOS dimerization and enzyme activity) and that this led to oxidative stress, uncoupling of nNOS, reduced NO levels, gastric nitrergic neuron dysfunction, and delayed gastric emptying compared to age-matched wild-type mice. These data support the notion that loss of NRF2 expression in diabetes impairs antioxidant gene expression, which deregulates NO synthesis, thereby contributing to the development of gastroparesis. We provide evidence that sex hormone, estradiol-17? (E2) mediated NRF2/nNOS expression and function is impaired in the onset of diabetes. In addition, we have shown that glycogen synthase kinase 3beta (GSK-3?) or E2 regulate the synthesis of NO in female stomachs. This data suggest that loss of NRF2 expression during hyperglycemia is a consequence of activation of a GSK-3?/CUL1/SCF/TrCP/RBX1 axis. Our central hypothesis is that nitrergic mediated gastric motility is regulated by NRF2. Specific Aim 1: will test the hypothesis that loss of NRF2 expression during hyperglycemia is a consequence of activation of a GSK-3?/CUL1/SCF/TrCP/RBX1 axis; Specific Aim 2: will test the hypothesis that restoration of NRF2 and NRF2-regulated antioxidant enzyme expression in diabetes will result in normal gastric motility and gastric emptying; and Specific Aim 3: will test the hypothesis that NRF2 and nNOS mediated gastric motility are regulated by female sex hormones; 17-estradiol (E2), progesterone and/or their gastric receptors in diabetic animals. Specific Aim 4: Investigate whether periodontal pathogens inhibit gastrointestinal (GI) motility in obese/diabetic female mice. The data from these studies will provide important information as to the mechanisms of regulation of NRF2-mediated nNOS function and thereby enhance our understanding of the pathophysiology of gastroparesis. The research outlined in these aims has translational relevance as it has the potential to identify novel treatment options for diabetes-induced gastroparesis.