The applicant has shown that (a) cells of the peripheral cardiac conduction system (CCS) or Purkinje fibers arise from differentiated cardiac myocytes; (b) differentiation of the peripheral CCS occurs invariably in the perivascular regions of the coronary arteries; and (c) Purkinje fibers do not share a common progenitor with cells of the central CCS. The applicant, therefore, hypothesizes that: (1) local factors arising from cells in the coronary vessels convert the contractile cardiac myocytes to form the conducting phenotypes of the peripheral CCS; (2) the network pattern of the coronary arteries defines the branching organization of the peripheral CCS; (3) since conduction cells induce skeletal muscle proteins and shut down cardiac muscle specific protein expression, Purkinje fiber differentiation involves a conversion of gene expression from a cardiomyocyte to a skeletal muscle program; and (4) the peripheral CCS is connected to the central CCS by in situ linkage, not by outgrowth from a common progenitor. In the proposed studies, the applicant would test these hypotheses experimentally in chicken embryos.
The specific aims are to: (1) determine mechanistic links between the branching pattern of coronary arteries and organization of the peripheral CCS; (2) characterize the conversion of gene expression from cardiac to skeletal muscle types during differentiation of the Purkinje fibers; and (3) identify the origin of the central CCS (AV bundles) and characterize its linkage to the peripheral CCS. The applicant's basic strategy in examining these mechanisms is to: (1) generate artificial coronary vessels in the myocardium of the embryonic heart (Aim 1); (2) determine expression patterns of skeletal muscle-specific genes during Purkinje fiber differentiation (Aim 2); and (3) complete retroviral cell lineage studies of the central CCS (Aim 3).
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