Project Summary/Abstract Although consistent physical activity is routinely prescribed to control hyperglycemia associated with type 1 diabetes (T1D), individual bouts of physical activity may increase the likelihood of evoking dangerous cardiovascular responses (i.e., heart attack and/or stroke). The long-term goal of this project is to elucidate mechanisms of autonomic dysfunction of cardiovascular control dur- ing physical activity to improve health and reduce mortality in those with T1D. The overall objec- tive is to determine the roles of P2X3Rs and ASIC3 on the exaggerated BP response to physical activity in males and females who are differentially afflicted by T1D and cardiovascular disease. The central hypothesis is that the effects of both P2X3Rs and ASIC3 on thin fiber muscle afferents contribute to the exaggerated exercise pressor reflex in T1D rats, an effect that changes with the pathophysiology of the disease. The rationale for this project is that understanding mechanisms of autonomic dysfunction of cardiovascular control, which present in response to physical activity, will lead to treating the temporal pathophysiology of T1D, thereby ameliorating risk of adverse cardiovascular events. The central hypothesis will be tested with three specific aims: 1) Determine the effects of metabolically sensitive P2X3Rs and ASIC3 on the altered exercise pressor reflex in T1D rats at different phases of the disease; 2) Determine the effects of metabolically sensitive P2X3Rs and ASIC3 on group III and IV afferent activity in T1D rats at different phases of the disease; 3) Determine the expression patterns of P2X3Rs and ASIC3 in the DRG neurons of T1D rats at different phases of the disease. For Aim 1, cardiovascular responses to muscle contraction will be measured in T1D rats before and after blocking or stimulating ASIC3 and P2X3Rs. For Aim 2, group III and IV afferent activity during muscle contraction will be measured in T1D rats before and after blocking or stimulating ASIC3 and P2X3Rs. For Aim 3, the location and expres- sion of ASIC3 and P2X3Rs on hindlimb DRG neurons will be determined using various biochem- ical techniques. The research proposed in this application is innovative because this will be the first study to determine the changing interactive effects of receptors and channels evoking reflex- ive blood pressure responses during exercise in both male and female T1D rats. Additionally, this study will be the first to analyze sex differences in blood pressure responses to exercise in T1D. The proposed research is significant because it will provide an initial understanding of possible mechanisms responsible for evoking the exaggerated exercise pressor reflex in T1D.