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Deciphering the Dynamic Notch Signaling Code

Award Number: R01HD075335
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/26/2012
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Deciphering the Dynamic Notch Signaling Code - Abstract The Notch signaling pathway directs cell fate decisions in diverse tissue contexts, plays key roles in disease, and represents a major drug target. The pathway uses multiple ligands and receptors that interact with one another in a promiscuous fashion, as well as Fringe glycosyltransferases that modulate those interactions. Recent work from our lab suggests that these interactions comprise a communication ‘code’ in which different ligands activate Notch receptors with distinct dynamics. These dynamics are, in turn, decoded to selectively activate distinct transcriptional target programs. Current understanding of the code is limited to just two ligands and one receptor. Determining how dynamic encoding occurs across a broader repertoire of ligand-receptor-Fringe combinations will enable better understanding, prediction, and control of signaling interactions between different cell types in diverse developmental and disease contexts. Here, we will combine cell line engineering, quantitative single-cell time-lapse imaging, direct control of Notch dynamics using mutant receptors and pharmacological perturbations, and analysis of Notch dynamics in neural stem cells and chick embryos to decipher this code and its functional roles. In Aim 1, we will focus on encoding, by mapping dynamic signaling modes across a full matrix of Notch receptor, ligand, and Fringe protein combinations. We will further extend this approach to analyze co-expression of multiple Notch receptors in the same cell, a pattern that occurs frequently in natural cell types. In Aim 2, we will focus on decoding, by computationally and experimentally investigating how cis-regulatory and trans-regulatory mechanisms together enable different signaling dynamics to selectively activate distinct target gene expression programs. Finally, in Aim 3 we will analyze the function of the Notch dynamic code in neurogenesis, using mouse neural stem cells and chick embryonic spinal cord development as model systems. In neural stem cells, using a combination of co-cultures, time-lapse microscopy, and end-point multiplexed single molecule RNA-FISH, we will map ligand-receptor combinations to Notch activity dynamics, and relate those dynamics in turn to cell fate decisions. In chick embryos, a Notch-specific fluorescent reporter, together with a new tissue slice preparation that enables imaging of individual living cells during spinal cord development, will enable us to link Notch dynamics to cell fate determination. Together, these results will reveal the structure and function of the dynamic code underlying Notch signaling, and show how it operates in key developmental contexts. More generally, they should help establish a paradigm for understanding signal encoding and decoding behaviors in cellular communication systems.


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: 2025 ( Subtotal = $0 )
2025	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	10	6/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $396,973 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	001	10	4/30/2024	NON-COMPETING CONTINUATION	$36,089
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	10	3/19/2024	NON-COMPETING CONTINUATION	$360,884
														Subtotal = $396,973

Issue Date FY: 2023 ( Subtotal = $400,983 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	9	2/15/2023	NON-COMPETING CONTINUATION	$400,983
														Subtotal = $400,983

Issue Date FY: 2022 ( Subtotal = $400,983 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	8	5/11/2022	NON-COMPETING CONTINUATION	$400,983
														Subtotal = $400,983

Issue Date FY: 2021 ( Subtotal = $400,983 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	001	7	3/26/2021	NON-COMPETING CONTINUATION	$0
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	7	2/11/2021	NON-COMPETING CONTINUATION	$400,983
														Subtotal = $400,983

Issue Date FY: 2020 ( Subtotal = $411,353 )
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	6	3/10/2020	COMPETING CONTINUATION	$411,353
														Subtotal = $411,353

Issue Date FY: 2019 ( Subtotal = -$84 )
2019	2016	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	5	12/14/2018	EXTENSION WITH OR WITHOUT FUNDS	-$84
														Subtotal = -$84

Issue Date FY: 2016 ( Subtotal = $338,951 )
2016	2016	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	5	6/14/2016	EXTENSION WITH OR WITHOUT FUNDS	$338,951
														Subtotal = $338,951

Issue Date FY: 2015 ( Subtotal = $333,815 )
2015	2015	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	4	5/19/2015	NON-COMPETING CONTINUATION	$333,815
														Subtotal = $333,815

Issue Date FY: 2014 ( Subtotal = $332,789 )
2014	2014	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	3	6/11/2014	NON-COMPETING CONTINUATION	$332,789
														Subtotal = $332,789

Issue Date FY: 2013 ( Subtotal = $324,915 )
2013	2013	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	2	6/17/2013	NON-COMPETING CONTINUATION	$324,915
														Subtotal = $324,915

Issue Date FY: 2012 ( Subtotal = $342,375 )
2012	2012	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	1	9/27/2012	NEW	$342,375
														Subtotal = $342,375

Grand Total All Awards = $3,684,036

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Deciphering the Dynamic Notch Signaling Code

Award Number: R01HD075335

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/26/2012

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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