Stroke is a leading cause of long-term disability in US and worldwide. Historically, both interventions and research have been focused on motor sensory deficits, while cognitive impairment, a decisive determinant of the quality of life for stroke survivors, has been rather neglected. Cognitive impairment is a major sequela after stroke, termed as post-stroke cognitive impairment (PSCI). Stroke and cognitive impairment are common among older persons with an estimate of 1/3 having different degree of cognitive impairment within several months after stroke. However, the prevalence of PSCI may have been significantly underestimated as the traditional Mini-Mental State Examination (MMSE) is not sensitive enough for cognitive assessment. Using more extensive assessment, recent clinical studies have indicated that PSCI is very common in both young and old stroke patients, even in cases of relative mild stroke and cases with excellent clinical recovery. The neuropathology of PSCI remains poorly defined and no FDA approved treatment is available for PSCI. Stroke is a heterogeneous disorder and the pathophysiology of PSCI should be interpreted with reference to clinical subtypes and brain changes in the sample. Accordingly, the mechanisms underlying PSCI should be explored using different stroke models. Our previous study has demonstrated that rats subjected to experimental ischemic stroke induced by transient middle cerebral artery occlusion (tMCAO), despite motor function recovery, developed progressive cognitive function deficit that correlates with hippocampal LTP suppression. A significant reduction of VEGF expression was found in the hippocampus after tMCAO. microRNA miR-20a/20b and 15a/b have been found to inhibit VEGF expression by targeting VEGF 3'-UTR. Consistently, increased levels of miR-15b and miR-20a were found in cerebral spinal fluid (CSF) and hippocampus at 30 days after tMCAO. Our preliminary study further demonstrated that treatment of miR-15b and miR-20a antagomirs at 1 week after stroke attenuated PSCI induced by tMCAO. Mounting evidence has indicated that VEGF enhance neurogenesis and hippocampus-dependent learning and memory. We hypothesize that focal ischemic stroke induces increase of miR-15a/b and ?miR-20a/b expression hence down-regulates VEGF expression in the hippocampus which contributes to PSCI. In the proposed studies, we will determine the effect of miR-15b and miR-20a antagomirs on PSCI induced by transient MCAO and the underlying mechanisms.
Aim 1 is to determine the tempo-spatial regulation of miR-15a/b, miR-20a/b and VEGF expression after ischemic stroke induced by transient MCAO.
Aim 2 is to determine the preventive effect of miR-15b and miR-20a antagomirs on PSCI induced by transient MCAO.
Aim 3 is to determine the VEGF-dependent effect of miR-15b and miR- 20a antagomirs on PSCI induced by transient MCAO.
Aim 4 is to determine the neurogenesis-dependent effect of miR-15b and miR-20a antagomirs on PSCI induced by transient MCAO.
Aim 5 is to determine if delayed treatment of miR-15b and miR-20a antagomirs reverses PSCI induced by transient MCAO.

Public Health Relevance

Cognitive impairment is a major sequela after stroke, termed as post-stroke cognitive impairment with no FDA approved treatment. In this application, we proposed to determine the effect and underlying mechanisms of small RNA molecules for the treatment of post-stroke cognitive impairment using experimental ischemic stroke models. The results derived from the proposed studies will provide critical insight for clinical applications of these medications for the prevention and treatment of post-stroke cognitive impairment after ischemic stroke in the near future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
1RF1NS109583-01
Application #
9642799
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2019-02-01
Project End
2024-01-31
Budget Start
2019-02-01
Budget End
2024-01-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of North Texas
Department
Other Health Professions
Type
Graduate Schools
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107