Social isolation (SI) predicts morbidity and mortality from a multitude of health conditions, including cancer, cardiovascular disease, and stroke. Patients with high levels of social support or large social networks exhibit more rapid and extensive functional recovery after stroke than socially isolated individuals, and the impact of these factors appears to be greater in elderly women. Social interaction overcomes the detrimental effects of SI by promoting adaptive behaviors and favorable neuroendocrine responses to biological stressors. Despite the huge impact of SI on post-stroke recovery, no study has attempted to mitigate the detrimental effects of isolation on neurobehavioral outcomes using target-based approaches. MicroRNAs (miRNAs) are short non-coding RNAs that are emerging as a powerful intervention tool for many diseases including stroke. They regulate a broad spectrum of biological pathways through fine-tuning of protein expression levels and altering gene expression levels. They have the ability to concurrently target multiple effectors of pathways involved in disease pathology. Very recent studies have found that microRNAs mediate many aspects of social interaction, leading us to hypothesize that miRNA regulation is involved in post-stroke pathology after SI. Preliminary studies have found that expression of several miRNAs including miR-181c-5p and miR-124-5p, which are involved in regulation of inflammation, long term potentiation and neurotrophin signaling, are modulated by post-stroke isolation in aged mice. In this proposal we will determine which miRNAs are differentially expressed in aged male and female mice isolated after stroke and determine if blocking (with genetic deletion or antagomirs) or enhancing (mimics) these target miRNA modulates their effects. The overall goal of this proposal is to determine if manipulation of target miRNAs can improve functional recovery after stroke in aged animals subjected to SI, a major risk factor for poor recovery.

Public Health Relevance

Social isolation (SI) is associated with increased mortality and morbidity in patients with established vascular disease, including stroke. Emerging evidence from experimental and clinical studies show that SI is not only a risk factor for stroke, but also contributes to increased stroke severity and delayed functional recovery. We will investigate the miRNAs that are differentially expressed after post-stroke isolation and determine common gene targets and attempt to block or mimic their effects in aged male and female mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS096493-04
Application #
9720945
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Bosetti, Francesca
Project Start
2016-09-30
Project End
2020-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Neurology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Verma, Rajkumar; Ritzel, Rodney M; Harris, Nia M et al. (2018) Inhibition of miR-141-3p Ameliorates the Negative Effects of Poststroke Social Isolation in Aged Mice. Stroke 49:1701-1707