PhD Oral Exam - Davindra Singh, Biology

When studying for a doctoral degree (PhD), candidates submit a thesis that provides a critical review of the current state of knowledge of the thesis subject as well as the student’s own contributions to the subject. The distinguishing criterion of doctoral graduate research is a significant and original contribution to knowledge.

Once accepted, the candidate presents the thesis orally. This oral exam is open to the public.

Abstract

Pathological left-ventricle hypertrophy (LVH) is a major contributor to heart failure, characterized by abnormal cardiomyocyte growth, which thickens the left ventricular wall and impairs cardiac contraction. Recent studies have demonstrated miR-1 downregulation in hypertrophic cardiomyocytes, establishing it as an early disease biomarker and a potential therapeutic target. Returning miR-1 to native levels presents a promising treatment strategy for LVH, however, safe and targeted delivery to the heart remains a significant challenge. Ultrasound-mediated delivery offers a non-invasive image-guided approach for cardiac-specific gene delivery.

In this thesis, I explore the use of ultrasound and microbubbles-mediated delivery of miR-1 for the treatment of LVH. First, using an in-vitro model, I optimized the delivery of miR-1 to diseased cardiomyocytes, ensuring a significant delivery while maintaining cell viability. These findings resulted in a reversion of hypertrophic phenotypes, including the expression of hypertrophic proteins, cytokines, and a restoration of cardiomyocyte size.

Building on these findings, an in-vivo delivery strategy was developed utilizing a clinical ultrasound system with clinically approved microbubbles. In healthy models, cardiac-specific delivery of miR-1 was observed with limited off-target effects. In hypertrophic models, a single treatment completely or partially reversed pathological phenotypes, including protein expression, serum cytokine levels, cardiomyocyte size, LV mass, heart function, mitochondrial respiration, and aerobic capacity. This study was performed in both sexes and revealed a more significant recovery in the male models.

Overall, this thesis highlights the feasibility of ultrasound and microbubbles delivery of miR-1 to the heart and elucidates the therapeutic potential of miR-1 for pathological left-ventricle hypertrophy.