Cardiac pacemaker cells of the sinoatrial node initiate and maintain the rhythmic beating of the heart. This function requires that pacemaker cells be insulated from, but also connected to, the working myocardium. While the mature sinoatrial node has been extensively studied, little is known regarding how sinoatrial node insulation is patterned during development. Understanding of how native pacemaker cells establish proper connectivity to the remainder of the heart, however, will provide critical insight for future pharmacological and cellular based therapies aimed at correcting sinoatrial node dysfunction and/or arrhythmic disorders. Therefore, this five year career development program is designed to serve two principle purposes: 1) to determine the cellular and molecular mechanisms that regulate sinoatrial node patterning during development, with emphasis on how pacemaker cells become electrogenically insulated, and 2) to provided support and training for the principle investigator, Dr. Michael Bressan, as he transitions from a postdoctoral fellow to an independent researcher. Specifically, this proposal will test the hypothesis that shortly after pacemaker cell differentiation in the embryo, a TGFb/BMP mediated fibrotic program initiates at the sinoatrial node periphery, which in turn insulates and protects central pacemaking cells from atrial myocytes. This will be tested in three specific aims which will a) define the developmental timing and physiological/molecular properties that generate sinoatrial insulation, b) determine the source(s) of the cell population responsible for this insulation, and c) test the requirement of TGFb and BMP for proper generation of this sinoatrial node patterning. Furthermore, this proposed project will allow Dr. Bressan to expand on his current research experience. Under the instruction of Dr. Takashi Mikawa, Dr. Bressan will explore the physiological and molecular mechanisms regulating sinoatrial node patterning at progressive developmental stages and be trained in advance techniques including retroviral mediated somatic transgenesis. Collectively, these studies will significantly advance our understanding of sinoatrial node development, while simultaneously allowing for Dr. Bressan to progress towards his long-term goal of becoming an independent researcher.

Public Health Relevance

Sinoatrial node dysfunction and other cardiac arrhythmias represent a major cause of morbidity and mortality in the United States. Future cellular and pharmacological interventions will depend on a detailed understanding of how native pacemaker cells are properly coupled to the remainder of the heart. This proposal, therefore, seeks to determine the largely unknown cellular and molecular mechanism that regulate developmental sinoatrial node patterning, specifically focusing on how pacemaker cells become insulated from adjacent myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
1K99HL122360-01
Application #
8677049
Study Section
Special Emphasis Panel (ZHL1-CSR-P (F1))
Program Officer
Wang, Wayne C
Project Start
2014-05-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$95,184
Indirect Cost
$7,051
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Bressan, Michael; Yang, PoAn Brian; Louie, Jonathan D et al. (2014) Reciprocal myocardial-endocardial interactions pattern the delay in atrioventricular junction conduction. Development 141:4149-57