Identification of immunotherapeutic targets in cardiovascular disease

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Project Summary. Myocardial infarction (MI) and neointimal hyperplasia (NH) are common comorbidities in patients with coronary heart disease - an insidious condition that comprises the majority of all cardiovascular disease (CVD)-related mortality. Following acute MI, occlusion of the coronary vasculature leads to persistent cardiac fibrosis and im- paired cardiac function. Restoration of coronary blood flow is often achieved by stent placement, but rates of excessive cellular ingrowth and pathologic NH formation remain high. Thus, optimal treatment strategies for acute MI must focus on reducing both cardiac fibrosis and neointima formation. Increasing evidence suggests inflammation regulates CVD progression, but little work has focused on the development of targeted immuno- modulatory therapies. Therefore, the objectives of this proposal are: 1) develop novel experimental and compu- tational approaches to identify and evaluate targeted immunotherapeutic treatment strategies in CVD and 2) establish a concentrated period of training that will equip Dr. Bersi with the expertise needed to transition to an independent research position. In the mentored K99 phase, Dr. Bersi will investigate how expression of the cell- cell adhesion protein cadherin-11 (CDH11) in diverse cellular lineages regulates inflammation and tissue remod- eling associated with MI and NH (Aim 1). By leveraging the immunomodulatory potential of CDH11, he will cor- relate tissue-specific remodeling with immune cell localization and cytokine secretion following concomitant car- diovascular injury. Experimentally-informed computational models of immune-mediated collagen deposition and smooth muscle cell proliferation will be used to identify the primary molecular and cellular drivers of tissue- specific injury responses (Aim 2). In the independent R00 phase, Dr. Bersi will utilize the proposed in silico models to generate novel immunotherapeutic hypotheses (Aim 2) and will evaluate model predictions by as- sessing the efficacy of rationally-designed immunotherapeutic treatments on the reduction of pathologic tissue remodeling in MI and NH (Aim 3). Though Dr. Bersi has significant expertise in soft tissue biomechanics and computational modeling, additional intellectual and technical training will be needed to realize his career goals of investigating the multiscale relationship between mechanics and inflammation in CVD. The Merryman and Harrison labs are ideal locations to acquire such training as Dr. Merryman is an expert in cardiopulmonary mech- anobiology and Dr. Harrison is an expert in cardiovascular immunology and pharmacology. The training received throughout this award will allow Dr. Bersi to successfully transition to an independent research position and lead a multi-faceted, R01-funded, research laboratory focused on mechanics, modeling, and inflammation in CVD. In summary, Dr. Bersi will utilize this K99/R00 award to establish multiscale experimental and computational tech- niques in order to guide the rational discovery and assessment of immunotherapeutic treatment strategies in inflammatory cardiovascular disorders. This project will lay the foundation for the use of targeted immunothera- pies in CVD and will define the trajectory of Dr. Bersi’s long-term career.