Uncovering the Mechanisms that Enable Cardiac Progenitors to Build the Linear Heart Tube

PROJECT SUMMARY Congenital heart defects (CHDs) occur in approximately 1% of newborns, resulting in life-altering consequences for those individuals and their families. Recent advances in genomics have led to the identification of numerous genes that are associated with CHDs. However, for many of these genes, it remains unclear what role they play in shaping the heart and how their dysregulation causes abnormal development. To understand the mechanisms that cause CHDs, and ultimately prevent or treat them, we need a better understanding of how the heart takes shape in the developing embryo. The primary objective of this K99/R00 proposal is to define the mechanisms by which cardiac progenitors build the linear heart tube. In Aim 1 (K99), PI Dr. Jonathon Muncie-Vasic will perform live-embryo imaging of normal mouse embryos and embryos with the CHD-associated gene, MEF2C, deleted. Cell segmentation and tracking will be used to quantitatively define the cell movements that are necessary for proper heart tube formation. In Aim 2 (K99), Dr. Muncie-Vasic will leverage multiomic datasets he generated during his postdoctoral fellowship to define the gene regulatory networks and identify novel regulatory elements that govern cardiac progenitor cell fates. In Aim 3 (R00), Dr. Muncie-Vasic will develop complementary in vitro and in vivo approaches to uncover how cell-matrix adhesions and mechanical tension regulate progenitor contributions to the heart tube. Together, these studies will provide important new insights into the cellular and molecular mechanisms that drive heart tube formation. The proposed research strategy is complemented by a career development plan that will provide Dr. Muncie-Vasic training in: i) Cell segmentation and tracking in live-embryo imaging datasets, ii) Experimental and bioinformatics approaches for dissecting gene networks, iii) Methods for interrogating adhesions and cellular tension, and iv) Inclusive mentorship and science communication skills. PI Muncie- Vasic will be well-supported in these efforts by his Mentor, Dr. Benoit Bruneau, an established leader in the field of cardiac development with a successful track record of guiding trainees to independence. To further promote his development, Dr. Muncie-Vasic has formed a Scientific Advisory Committee with wide-ranging expertise, consisting of Drs. Deepak Srivastava (cardiac disease, clinical background), Brian Black (cardiac development and regeneration), Christina Theodoris (machine learning, clinical background), and Jeffrey Bush (regulation of morphogenesis). With the integrated research strategy and career development plan of this K99/R00 proposal, along with the distinguished mentorship team and world-class environment at Gladstone Institutes, Dr. Muncie-Vasic is positioned to successfully establish an independent research program defining the physical mechanisms that drive morphogenesis of the developing heart.