Gooch Awarded $154K from the American Heart Association

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BME Associate Professor Keith Gooch, in collaboration with Dr. Pam Lucchesi, (Nationwide Children’s Hospital), was recently awarded a two year grant in the amount of $154K from the American Heart Association (AHA) for a project entitled, "Matrix stiffness and cardiac fibroblast phenotype”. BME Associate Professor Jun Liu, serves as a consultant for their collaborative work studying cardiac fibroblasts. 

The projects brief description and abstract follows: Changes in blood flow and pressure and the associated in the mechanical environment of the heart can trigger progressive heart failure. Our studies will focus on understanding the molecular mechanisms regulating cell dysfunction in response to these mechanical changes at an early time point before heart failure has begun. The rationale for choosing this early time point for study is that a better understanding of the key molecular pathways could allow pharmacological treatment of patients at this early stage thereby limiting adverse remodeling in heart failure progression. We are asking two specific questions: 1) what are the major effects of reduced tissue stiffness on cadiac fibroblasts’ ability to make and remodel structural proteins important in normal heart structure and function? and 2) what are the molecular changes responsible for the changes in the cardiac fibroblasts? To answer these questions, we will use a combination of animal and cell culture studies. 
  
Abstract: Cardiac fibroblasts (CFs) are the most abundant cell type in the heart and display considerable plasticity, allowing them to adapt to extracellular cues such as growth factors, neurohormones, and mechanical stress. Under normal conditions, CFs regulate a dynamic balance between ECM deposition and degradation in order to maintain proper left ventricular structural and mechanical stability. In response to myocardial injury and mechanical stress, CFs undergo phenotypic differentiation in an attempt to repair and preserve myocardial structural integrity. Under chronic stress, however, these CF changes contribute to adverse ventricular remodeling and ultimately heart failure. Our long-term goal is to understand how the CF phenotype can be manipulated by therapeutic intervention to treat diseases associated with adverse cardiac remodeling. During volume overload, there is a loss of ECM in the ventricle leading to dilation and reduced tissue stiffness. This loss of matrix is perplexing, since levels of pro-fibrotic factors including TGFβare elevated. Our preliminary data indicates that relative to CF isolated from healthy hearts, CF freshly isolated from volume overload hearts have reduced basal matrix synthesis and reduced responsiveness to TGFβ. Similarly, CFs isolated from healthy hearts have reduced matrix synthesis and responsiveness to TGFβ when cultured on softer substrates. In both cases, the transition of the cells toward a hypo-fibrotic phenotype appears to be accompanied with changes in the expression and distribution of key transcriptional regulators including MRTF-A, YAP, and PPARγ. Based on these and other observations, we reason that matrix stiffness is a key regulator of CF phenotype and decreased matrix stiffness contributes pathological remodeling of hearts exposed to overload. Our proposed studies will explore the cytoskeleton and gene expression as key nodes that regulate CF responses to substrate stiffness. 


Congratulations to Drs. Gooch, Lucchesi, and Liu!