This proposal describes a five-year training program for development of a research career in cardiovascular developmental biology. The candidate is a cardiology fellow at the University of Pennsylvania with an M.D./Ph.D. in molecular biology. She is currently engaged in intensive basic science research supported by the Ruth L. Kirschstein National Research Service Award (T32), and additionally receives institutional support from the Department of Medicine Measey Basic Science Fellowship Award. The proposed research will enhance our understanding of congenital heart disease and arrhythmias. It will be carried out under the mentorship of Jonathan Epstein, M.D. a recognized leader in the field of cardiac development. He is a professor of Medicine, and the scientific director of the University of Pennsylvania Cardiovascular Institute (CVI). He has mentored numerous postdoctoral fellows and graduate students. An advisory committee of talented clinician-scientists has been assembled to offer guidance in career development and science. The environment of Penn and the CVI provides extensive resources, collaborations, core facilities and intellectual expertise. This is an ideal training setting to develop a skill set in order to transition to an independent career as an academic physician- scientist. Participation in didactic courses and faculty professional development seminars will enhance the educational success of the program. Wolff-Parkinson-White (WPW) syndrome occurs when an electrically active connection apart from the AV node-His pathway exists between the atria and ventricles, resulting in ventricular pre-excitation and often leading to symptomatic tachycardias or sudden death as the first clinical manifestation. Despite its initial description over sixty years ago, little is known about the causative mechanisms underlying the formation of these accessory electrical connections due in part to a paucity of animal models. The candidate has developed a clinically relevant murine model of WPW through activation of Notch signaling in a subset of cardiomyocytes. Notch signaling is an evolutionarily conserved pathway that has been implicated in many aspects of development and disease, including the pathogenesis of many malignancies, as well as cardiac developmental defects such as bicuspid aortic valve and tetralogy of Fallot. However, a role for Notch in arrhythmic phenotypes has not previously been described. Characterization of this novel model will simultaneously provide insight into the pathogenesis of WPW and will provide a platform for studying potential therapeutic interventions.
The aims of the proposal are: 1) To test the hypothesis that Notch signaling regulates formation of accessory pathways and cardiac electrophysiologic properties via both cell autonomous and non cell-autonomous mechanisms, and 2) To test the hypothesis that constitutive activation of Notch results in WPW through abnormal patterning of AV canal myocardium. Completion of the studies outlined in this proposal will bridge a vital gap in knowledge that may ultimately translate into the availability of more advanced molecular genetic studies and improved diagnostic and therapeutic options for WPW patients.
Wolff-Parkinson-White syndrome is a relatively common disease affecting children and young adults and, despite its initial description over sixty years ago, little is known about the causative mechanisms underlying the formation of accessory pathways. This grant proposes to study a novel animal model of Wolff-Parkinson- White syndrome to gain important insight into the developmental abnormalities at the tissue and molecular level leading to this syndrome. The ultimate goal is to apply the lessons learned from the study of embryonic development and translate them into more advanced molecular genetic studies and improved diagnostic and therapeutic options for patients.
|Qiao, Yun; Lipovsky, Catherine; Hicks, Stephanie et al. (2017) Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice. Circ Res 121:549-563|
|Meyers, Jason D; Jay, Patrick Y; Rentschler, Stacey (2016) Reprogramming the conduction system: Onward toward a biological pacemaker. Trends Cardiovasc Med 26:14-20|
|Khandekar, Aditi; Springer, Steven; Wang, Wei et al. (2016) Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents. Circ Res 119:1324-1338|
|Díaz-Trelles, Ramón; Scimia, Maria Cecilia; Bushway, Paul et al. (2016) Notch-independent RBPJ controls angiogenesis in the adult heart. Nat Commun 7:12088|
|Gillers, Benjamin S; Chiplunkar, Aditi; Aly, Haytham et al. (2015) Canonical wnt signaling regulates atrioventricular junction programming and electrophysiological properties. Circ Res 116:398-406|
|Boukens, Bastiaan J; Rivaud, Mathilde R; Rentschler, Stacey et al. (2014) Misinterpretation of the mouse ECG: 'musing the waves of Mus musculus'. J Physiol 592:4613-26|
|Gerhardt, Dawson M; Pajcini, Kostandin V; D'altri, Teresa et al. (2014) The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells. Genes Dev 28:576-93|
|Smith, Amanda W; Hoyne, Jake D; Nguyen, Peter K et al. (2013) Direct reprogramming of mouse fibroblasts to cardiomyocyte-like cells using Yamanaka factors on engineered poly(ethylene glycol) (PEG) hydrogels. Biomaterials 34:6559-71|
|Addis, Russell C; Ifkovits, Jamie L; Pinto, Filipa et al. (2013) Optimization of direct fibroblast reprogramming to cardiomyocytes using calcium activity as a functional measure of success. J Mol Cell Cardiol 60:97-106|
|Rentschler, Stacey; Yen, Alberta H; Lu, Jia et al. (2012) Myocardial Notch signaling reprograms cardiomyocytes to a conduction-like phenotype. Circulation 126:1058-66|
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