Current treatment options for the spectrum of cognitive disorders brought about by vascular disease, termed vascular contributions to cognitive impairment and dementia (VCID), are limited due to a fundamental gap in understanding the underlying mechanisms. Our long-term goal is to elucidate key mechanistic drivers of VCID to identify potential therapeutic targets. The objective of this application is to explore the mechanisms underlying the role of brain insulin in vascular function in a model of insulin resistance and VCID. The central hypothesis is that elevated levels of endothelial protein tyrosine phosphatase 1B (PTP1B) reduces insulin transport and signaling contributing to cerebrovascular dysfunction and VCID. This hypothesis is based on preliminary data produced in the applicant’s laboratory. The rationale for the proposed research is that understanding the mechanisms underlying reduced brain insulin levels and signaling and its impact on vascular function may lead to innovative approaches to ameliorate VCID. This hypothesis will be tested by pursuing two specific aims: 1) test the hypothesis that elevated levels of PTP1B in endothelial cells reduces brain insulin levels and signaling, thereby reducing vascular function and 2) test the hypothesis that increasing brain insulin levels restores cerebrovascular function reversing VCID. Under Aim 1, insulin levels/signaling using molecular techniques and structural/functional changes using multiphoton imaging in capillaries will be assessed in young and middle-aged transgenic mice lacking PTP1B in endothelial cells on either a standard diet or high-fat diet (model of insulin resistance). Under Aim 2, cerebrovascular function, assessed via measuring cerebral blood flow, neuronal activity, and cognition, and functional recovery, assessed via evaluating survival, neurological, and sensorimotor function, will be examined in a young and middle-aged insulin resistant mouse model of VCID (middle cerebral artery occlusion model of stroke). The approach is innovative because of the study design, combination of methods, use of intranasal insulin, and focus on PTP1B as a mechanism underlying reduced brain insulin levels/signaling and vascular dysfunction associated with VCID. The proposed research is significant because it is expected to lead to the development of therapies targeted to key mechanisms underlying cerebrovascular dysfunction and VCID.