# Targeting brain insulin to improve stroke-related vascular contributions to cognitive impairment and dementia

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2024 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10720889
- **Project number:** 5I01BX005666-02
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Catrina Sims Robinson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10720889

## Citation

> US National Institutes of Health, RePORTER application 10720889, Targeting brain insulin to improve stroke-related vascular contributions to cognitive impairment and dementia (5I01BX005666-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10720889. Licensed CC0.

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