Dissecting input-output relationships of Developmental BMP Signaling

NIH RePORTER · NIH · K99 · $104,838 · view on reporter.nih.gov ↗

Abstract

ABSTRACT A small number of conserved signaling pathways are key players in cell fate decisions that govern embryonic development, maintenance and health of adult tissues, and progression of disease states. For example, embryonic development in numerous species hinges on the dynamics and regulation of the BMP signaling pathway. Our current knowledge of BMP signaling pathway specificity is based upon foundational genetic and in vitro experiments, but we have limited understanding as to how cells produce diverse but specific responses to similar signaling inputs in vivo. In the Drosophila embryo, a steep gradient of BMP signaling is dynamically established prior to gastrulation. This gradient is interpreted by different populations of cells to establish the dorsal-ventral axis of the embryo, with cells at the dorsal midline turning on a unique set of transcripts compared to more lateral cells. We do not know how the dynamics of gradient formation and the final gradient pattern are interpreted by cohorts of cells in the embryo to produce the correct spatiotemporal transcriptional response. This study aims to shed light on how cells perceive and respond to varying BMP signaling inputs, with the goal that these discoveries will be broadly applicable to other biological contexts. The proposed research program employs cutting-edge quantitative live imaging techniques, the creation of predictive mathematical models, and the adaptation of tools for studying BMP signaling in diverse insect species. Specifically, I will develop a predictive model for BMP target gene transcription that can correlate BMP signaling dynamics with timing and spatial patterns of gene expression. Second, I will examine crosstalk between BMP signaling and EGFR/ERK signaling by developing live imaging approaches and applying quantitative methods. Finally, I will expand the research scope by building tools to examine BMP signaling dynamics in the red flour beetle, Tribolium casteneum. By leveraging the unique characteristics of Tribolium, such as slower development and distinct embryonic tissue architecture, I will elucidate how the conserved BMP signaling pathway adapts and functions across species. The proposed multi-faceted approach, ranging from mathematical modeling to cross-species comparisons, promises to unveil fundamental principles of cell signaling and provide a foundation for further advancements in developmental biology and translational applications. To accomplish these goals, I have formed an exceptional committee of advisors who can aid in my diverse approach to understanding signaling dynamics in vivo. Together with my advisor, Dr. Stefano Di Talia, I have designed a training plan that will provide me with the skills required to run a productive, independent laboratory that tackles complex questions about the role of conserved signaling in developmental biology.

Key facts

NIH application ID
10949362
Project number
1K99HD115781-01
Recipient
DUKE UNIVERSITY
Principal Investigator
Susanna Elizabeth Brantley
Activity code
K99
Funding institute
NIH
Fiscal year
2024
Award amount
$104,838
Award type
1
Project period
2024-08-01 → 2026-07-31