Patil, Rohan Mahesh (2026) Circadian Regulation of Stroke Pathophysiology and Non-coding RNA Signatures in Human and Experimental Models. [Tesi di dottorato]

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Abstract

Stroke remains a leading cause of death and long-term disability, and outcomes differ markedly depending on the time of day the event occurs. Emerging evidence suggests that circadian rhythms shape vascular physiology, immune activity, and neuronal vulnerability. Yet, the molecular mechanisms linking circadian timing to stroke severity remain poorly understood. This thesis combines human clinical studies, a randomized controlled trial, and preclinical experimental models to investigate how circadian timing influences ischemic injury, immune responses, and non-coding RNA signatures with particular focus on microRNAs (miRNAs) and PIWIL-interacting RNA pathways. In Study 1, acute ischemic stroke patients stratified by day versus night onset demonstrated distinct circulating miRNA profiles. Several miRNAs correlated with infarct volume, metabolic derangements, and inflammatory markers, highlighting temporal gating of stroke biology. Study 2, a phase-ll randomized trial of remote ischemic conditioning (RIC), showed that RIC modulated circulating miRNAs over 24–72 hours, providing molecular evidence of remote protection in patients who were not subjected to reperfusion therapy. In Studies 3 and 4, transcriptomic and small RNA sequencing in mouse models revealed region-specific and time-dependent gene disruption, mitochondrial vulnerability, immune activation, and ischemia-induced modulation of PIWIL proteins. Silencing of PIWIL2 reduced infarct volume and altered chemokine responses, implicating a novel role for somatic PIWIL pathways. Together, these findings demonstrate that circadian timing gates ischemic injury and systemic inflammatory signaling, modulates circulating RNA biomarkers, and reveals the PIWIL/piRNA axis as a potential regulator of post-stroke immune responses. This integrative framework provides translational insights for time-of-day diagnosis, biomarker-guided treatment, and the development of novel molecular therapies.

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