Central and Peripheral Transcriptomic Networks Driving Cardiovascular Control
Cardiovascular disease is a widespread systemic disease that contributes substantially to morbidity and mortality rates both in the United States and across the globe, with hypertension being a major contributing factor. While multiple organ systems have been found to contribute to the development of high blood pressure and cardiac dysfunction, increased sympathetic nerve activity stemming from the higher centers of the autonomic nervous system is considered to be one of the earliest indicators. The work presented in this thesis explores the cardiac control circuit and the gene regulatory networks at the central and peripheral levels that drive cardiovascular function. In the central nervous system (CNS), we focus our investigation on three autonomic nuclei in the brainstem, the nucleus of the solitary tract (NTS), the caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM). These regions coordinate sympathetic and parasympathetic outflow to the heart which is altered in the hypertensive state. We dissect the miRNA and gene regulatory networks underlying this dysfunction starting prior to the onset of the hypertensive phenotype to robust hypertension. By examining the networks that both drive and sustain hypertension, we identify the dominant pathways at the various stages of hypertension development with the goal of informing potential therapeutic interventions. Given the recent interest in miRNAs as therapeutic targets for a variety of physiological conditions, we focus on miRNAs with the potential to influence multiple pathways known for driving autonomic dysfunction. On the other end of the cardiac control circuit in the peripheral nervous system, we characterize the single neuron anatomical and molecular networks in the intrinsic cardiac nervous system (ICNS) in the heart. Until now, our knowledge of the ICNS has been largely limited to physiological signaling and establishing a molecular basis for cardiac control at the heart enables a wide range of studies to uncover shifts in the molecular network that lead to cardiac dysfunction. Collectively, this work expands our knowledge of the cardiac control circuit at the central and peripheral levels, enabling future studies that can connect the CNS and ICNS to build a systems-level understanding of cardiovascular function and disease.
Moss, Alison Rachel, "Central and Peripheral Transcriptomic Networks Driving Cardiovascular Control" (2021). ProQuest ETD Collection - Thomas Jefferson University. AAI28863554.