Molecular Mechanisms of microRNA-494 Involving in Cerebral Ischemia

Study Overview
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Brief Summary
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We and other investigations suggested that the activation of nerve cell cycle following cerebral ischemia led to neuronal apoptosis, glial cell proliferation and the formation of glial scar.The cyclin-dependent kinases (CDKs) and cyclins jointly promoted the cell cycle progression. Our preliminary clinical trial found a new microRNA-miR-494, which involved in the occurrence of acute ischemic stroke. In our animal experiment, miR-494 could relieve cerebral ischemia injury through inhibiting cyclin-dependent kinase 6(CDK6), ubiquitin-conjugating enzyme E2L6 (UBE2L6) and histone deacetylase 3 (HDAC3), which suggested that miR-494 might play an important role in the regulation of cell cycle following cerebral ischemia. This project intends to verify the following hypothesis：①miR-494 suppresses CDK6, and/or fibroblast growth factor16(FGF16)-Ras-extracellular signal-regulated kinase(ERK)--v-myc avian myelocytomatosis viral oncogene homolog(MYC) pathway, and/or phosphatase and tensin homolog(PTEN)-/protein kinase B(AKT)-mechanistic target of rapamycin(mTOR)-S6k pathway;②miR-494 inhibits UBE2L6, upregulates the hypoxia-inducible factor 1 α(HIF-1α) expression in nerve cells, thereby increases the p21 and p27 protein levels and inhibits cyclin-dependent kinase2(CDK2)activity;③miR-494 represses HDAC3 and downregulates the cyclin-dependent kinase1(CDK1)protein level. These all mediate the cell cycle arrest of neurons and astrocytes, reduce the neuronal apoptosis and glial scar formation,promote the recovery of neurological function and provide new targets for the treatment of ischemic stroke.

Official Title
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Study on the Molecular Mechanism of miR-494 Mediating Cell Cycle Regulation Following Cerebral Ischemia

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Other: There is no intervention at all.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (1）diagnosis of first ischemic stroke based on clinical information and magnetic resonance imaging; (2)presentation of subjects within 6h of the event; (3)National Institutes of Health Stroke Scale (NIHSS) score between 4 and 15. Exclusion Criteria: (1）suspected cardiogenic embolism;(2）secondary stroke from cerebral hemorrhage, trauma, cancer or aneurysm and so on;(3）bleeding tendency;(4）severe cardiac,pulmonary,hepatic or renal insufficiency;(5）Vital signs are unstable to be assessed.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ischemic stroke<br>acute ischemic stroke patients within 6h after stroke onset | Other: There is no intervention at all.<br>* There is no intervention at all.<br>|
| control<br>healthy controls | Other: There is no intervention at all.<br>* There is no intervention at all.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the molecular mechanism of miR-494 mediating cell cycle regulation following cerebral ischemia |  | through study completion, an average of 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, miR-494, neuroprotection, CDK