NIH-R25 Summer Program for Undergraduate Research

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Presentation transcript:

NIH-R25 Summer Program for Undergraduate Research Transcriptional Regulation of Heart Valve Development: The Roles of VEGF and NFAT Signaling Ben Smood University of Oregon Stankunas Lab NIH-R25 Summer Program for Undergraduate Research

Outline Significance Development Known Roles of VEGF and NFAT signaling Methods, Goals, and Plans Questions

Significance Heart valve defects in 2-3% of population Bicuspid aortic valve disease Mitral valve prolapse VSD Single Set of Valves Effected Egyptians: wisdom VSD congenital-hypertension, heart failure, delayed growth and development Starts beating at E18humans, pumping blood by E21 DSCR1 encodes inhibitor of calcineuron DYRK1a promotes NFATc export

E9.5-10.5 EMT (major cushions seen at end) E10.5-13.5 Cushion proliferation 13.5-18.5 elongation and remodeling GET NEW FIGURE FROM BOOK

Valve Formation

VEGF and Valve Formation Lambrechts and Carmeliet 2004

NFATc1: What’s Known Zeini et al. 2009

NFAT Signaling Chang et al. 2004 Endocardial NFATc blocks VEGF in myocardium Lose NFATc1 when mesenchymal cells; gone in EC after E13.5 NFATc1 for Emt only in OFT valves Directly represses VEGF-A gene No general angiogenic defects seen with inhibtion of VEGF signaling (VEGF-A is associated with angiogenesis though) DSCR1 encodes inhibitor of calcineuron DYRK1a promotes NFATc export Chang et al. 2004

Slight differences have tremendous impacts sFlt-sequesters VEGFR1 ligands (sensitive emt) VEGFR2T-sequesters VEGFA, not VEGFB or plgf (not sensitive) Placental growth factor

What are the transcriptional factors targeted by VEGF and NFATc1 signaling?

Aims: Understand the Roles of VEGF and NFATc1 in Development Small molecule Inhibitors Small molecule pharmagrade Cyclosporine A, Cabozantinib, Sunitinib TU-Tagging Spatial & Temporal transcriptional events Cabo inhibit vegfr2 phosphorylation Suni VEGFR blocks

Double outlet right ventricle

A floxed-stop-UPRT line for modular cell-specific TU-tagging in mice Uracil phosophoribosyltransferase (ribose-5 phosphate to N1 nitrogen of Uracil. incorporated)

First method to covalently label RNA within specific cell types in the intact mouse

Acknowledgements Stankunas Lab SPUR Dr. Peter O’Day NIH-R25 Dr. Kryn Stanuknas Dr. Scott Stewart Vidusha Devasthali Fern Bosada Brynn Simeck Alex Ackerberg Maithri Sarangam Alan Gomez Cho Li SPUR Dr. Peter O’Day NIH-R25 Peter O