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Mechanisms of signal integration in developmental control of organ size and tissue patterning

Award Number: R01GM141843
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Mechanisms of signal integration in developmental control of organ size and tissue patterning - PROJECT SUMMARY/ABSTRACT The proposed work will investigate transcriptional interpretation of signaling through the ERK pathway, which plays critical roles in animal development and is commonly deregulated in human diseases. We will use Drosophila as an experimental model that offers unrivaled opportunities for dissecting gene regulation by ERK signaling at multiple levels of biological organization, from specific ERK substrates to the whole embryo. Aim 1 focuses on Capicua (Cic), a transcriptional repressor that was discovered in Drosophila and has recently emerged as a key sensor of ERK activation in developmental and pathological contexts. We will identify functionally significant phosphorylation sites in Cic and investigate their effects on the ERK-dependent control of Cic protein stability, nuclear localization, and DNA binding. Aim 2 is designed to bridge the gap between genetic studies, which commonly identify only a handful of ERK substrates, and omics-level studies, which suggest that ERK functions through large substrate cohorts. We will evaluate these two scenarios using an already working combination of acute optogenetic perturbations, quantitative phosphoproteomics, and live imaging of functionally significant transcriptional responses to ERK signaling. Finally, Aim 3 will study transcriptional effects of ERK signaling, which commonly works by simultaneously activating some cell fates and repressing others. We will use quantitative optogenetic perturbations and live imaging to test the hypothesis that activating and repressing effects of ERK signaling require different levels of ERK activation. Our experimental tests of this hypothesis will address a key issue in developmental ERK signaling and will provide quantitative data needed for predictive computational modeling. Feasibility of the proposed work is supported by preliminary data that include functional characterization of Cic phosphosites (Aim 1), a phosphoproteomics approach for the in vivo discovery of ERK substrates (Aim 2), and an optogenetic approach to data-driven design of predictive computational models (Aim 3).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $308,144 )
2024	2024	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Biomedical Research and Research Training	000	9	7/30/2024	NON-COMPETING CONTINUATION	$308,144
														Subtotal = $308,144

Issue Date FY: 2023 ( Subtotal = $308,144 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Biomedical Research and Research Training	000	8	7/24/2023	NON-COMPETING CONTINUATION	$308,144
														Subtotal = $308,144

Issue Date FY: 2022 ( Subtotal = $354,801 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Biomedical Research and Research Training	001	7	7/20/2022	NON-COMPETING CONTINUATION	$308,144
2022	2021	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Biomedical Research and Research Training	000	6	2/1/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$46,657
														Subtotal = $354,801

Issue Date FY: 2021 ( Subtotal = $318,616 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Biomedical Research and Research Training	000	6	9/1/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$318,616
														Subtotal = $318,616

Grand Total All Awards = $1,289,705

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Mechanisms of signal integration in developmental control of organ size and tissue patterning

Award Number: R01GM141843

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/05/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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