CardioPulmonary Vascular Biology COBRE

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Cardiopulmonary Vascular Biology COBRE Team Science Supplement Project Summary: Goal of the parent award: The vision of the CardioPulmonary Vascular Biology (CPVB) COBRE program is to develop effective approaches to prevent and treat vascular diseases affecting the pulmonary and cardiovascular systems through better understanding of disease mechanisms. This is accomplished by serving as an interdisciplinary center which promotes collaborative research and provides excellent technical support and resources to investigators. The overall mission of the CPVB COBRE program has been to build the human and technical infrastructure and services that serve as catalysts to increase CPVB research in the state. Cardiovascular and pulmonary diseases are among the leading causes of morbidity and mortality in the US and in the world. Thus, there is an important need to understand the pathogenesis of cardiopulmonary vascular diseases in order to develop more effective treatments and prevention. The overall goal of the CPVB COBRE program is to facilitate high impact vascular biology research. The CPVB COBRE program provides infrastructure with administrative, pilot project, and two technical cores, thus providing opportunities to expand areas of investigation, experimental and technical approaches, and scientific collaborations. The specific aims of Phase III CPVB COBRE are to: i) award high-impact research projects in the area of cardiopulmonary vascular biology; ii) provide effective and high-quality services in cell isolation and ex vivo organ function (CIOF), mitochondrial function, and in vivo imaging (MF-II); iii) collaborate with IDeA programs in Rhode Island (RI) and other states to foster scientific networks by providing programming, funding, technical services, and resources to enhance research productivity; and iv) maintain a robust line of investigation in vascular biology that meets the needs of the scientific community and furthers research in prevention and treatment of cardiopulmonary vascular diseases. We will expand and enrich the vascular biology research community by promoting new collaborations and engaging scientists new to the field from a variety of disciplines. At the end of Phase III, we expect to transition to a sustainable CPVB Center serving as a home to the CVPB research community with high quality core services, significant institutional support, and commitment to continue the development of effective approaches to combat or resolve cardiopulmonary vascular diseases. Research question to be addressed by the supplement award: Right Ventricular (RV) dysfunction in settings of pulmonary hypertension (PH) is associated with poor outcomes irrespective of associated comorbidities and underlying conditions. PH is common and afflicts ~ 1 % of world population, is commonly associated with cardiopulmonary diseases, and in many cases is associated with pulmonary vascular remodeling. Despite the known poor prognosis associated with RV dysfunction, to date, no RV targeted therapies are available, and the underlying mechanisms of RV dysfunction remain unclear. Therefore, there is an unmet need for a better understanding of cellular and molecular mechanisms associated with RV dysfunction and to convert this knowledge into therapies. Pathophysiological mechanisms associated with RV dysfunction include changes in cellular composition of the myocardium, matrix remodeling (e.g., fibrosis), metabolic dysfunction resulting in heart failure and ventricular and atrial arrhythmias. While reductionist approaches have resulted in important insights into role of specific cell types and signaling pathways, a comprehensive evaluation using multi-scale and multi- omics evaluation and use of novel data-science analytical techniques to identify the networks and pathways that underlie maladaptive RV and RV dysfunction has not been performed and is the overall objective of this proposal. Why need for team science effort? Considering the multiple pathophysiological mechanisms, cell types and phenotypes (arrhythmia, energetic and mechanical failure) associated with RV dysfunction, there is need to bring together experts in myocardial biology, mitochondrial biology, and arrhythmia biology. Furthermore, use of large unbiased datasets to unravel novel networks and pathways underlying RV dysfunction requires analytical and methodological expertise in reducing the dimensionality of data and identification of important multi-omic network features using novel artificial intelligence based methodology that relate with the maladaptive phenotypes in settings of RV dysfunction. These data, approaches and collaborations are expected to result in multi-PI and program project grant applications that will lead to sustainable teams to perform impactful scientific investigation in cardiopulmonary vascular diseases such as RV dysfunction and failure.