Klf2/4 and mechanical signaling in cardiac fibroblasts - Project Summary As the body’s systemic circulatory pump, the heart undergoes billions of contraction-relaxation cycles in the lifespan of an individual. This steadfast systolic and diastolic function is owed to cardiomyocytes (CMs) and in-between (“interstitial”) cells such as cardiac fibroblasts (cFBs) and the extracellular matrix (ECM) they produce. Cardiovascular (CV) diseases are the most common causes of mortality worldwide, and congestive heart failure (HF) makes up a a significant proportion of CV deaths. HF is associated with cFB activation, fibrosis, and ECM stiffening, and carries a substantial burden of morbidity, hospitalization, and mortality. Therefore, establishing new therapies for prevention and reversal of HF (among other diseases) will require greater knowledge of cFB function and homeostasis. Using unique mouse models of cardiac loading and unloading, I have found that levels of transcription factors Klf2 and Klf4 within resting (“quiescent”) cFBs are responsive to pressure and volume changes in the myocardium. I have also found that fibroblast-specific deletion of Klf2/4 in mice causes enlargement and thinning of the cardiac ventricle, a process known as eccentric remodeling that is commonly observed in HF. Loss of Klf2/4 in cFBs also results in histological changes to collagens and ECM proteoglycan, leading to progressive injury and fibrosis over time. A better understanding of Klf2/4 mechano-responsive function in cFBs, including roles for their effector genes, will shape clinical and translational pursuits in diseases like HF. The proposed research will advance my skills in modeling adult cardiovascular physiology and pathology – both in vitro and in vivo. As my prior postdoctoral research was in developmental biology, I will use the award period to pivot my career toward adult cardiac homeostasis and pathology, and to grow into an independent scientist within the training environment of my primary mentor, Dr. Mark Kahn, and the University of Pennsylvania Cardiovascular Institute (Penn CVI). I will also gain immense knowledge and wisdom from my advisory committee, which is made up of esteemed researchers (including CVI cardiologist-scientists) with expertise in heart failure, metabolism, collagens, and cFBs. Besides gaining experience in adult cardiac physiology and disease, which is new for me, I will undertake a career development plan with active mentorship, international presentation and networking, as well as leadership and lab management training. The proposed studies will establish new models of cFB mechanical signaling, and will probe Klf2/4 function in the heart in health and disease. By understanding how Klf2/4 affects cFB signaling, activation, and synthesis, this work will uncover potential pathways and molecules of therapeutic value. Moreover, I anticipate generating new tools and unbiased datasets during the award period that will become the underpinnings of my early career as an independent investigator.
