Friday, July 4, 2025 7/4/2025

Center for Cell Circuits

Award Number: RM1HG006193
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/09/2011
PERIOD OF PERFORMANCE END DATE: 04/30/2022

Group Awards By:

View Award Description

Center for Cell Circuits - DESCRIPTION (provided by applicant): Reconstructing the circuits that control how cells detect environmental triggers and adopt specific fates is a fundamental challenge across all areas of biology. Genomic research on circuitry has initially used observational approaches that infer regulation from correlations in molecular profiles, but cannot distinguish correlation from causation. Our Center has developed and successfully demonstrated an approach that uses single perturbations to determine the function of individual components. However, because interactions in circuits are non-linear, we cannot predict how the circuit will function simply by summing up these individual effects. What is needed is a massive combinatorial analysis: perturbing multiple genes simultaneously, with a compatible genomic readout. To take on this apparently intractable problem, we need to radically boost the type and scale of our experimental and analytic methods. Several advances from our groups and others provide an unprecedented framework for such massively parallel, high order combinatorial circuit analysis based on millions of experiments. First, the CRISPR/Cas9 system enables large-scale pooled, multi-locus gene perturbation in mammalian cells. Second, massively-parallel single cell genomics and proteomics, based on combinatorial bead barcoding and gel droplet microfluidics, allow global readouts from hundreds of thousands to millions of cells. Third, the mathematical theories of random matrices and compressive sensing justify substantial reduction in the sampling of an otherwise enormous combinatorial space under biological realistic and testable hypotheses. Here, we will develop a set of Massively Parallel Combinatorial Perturbation (MCPP) assays, as cost-effective methods to measure genomic profiles in individual cells commensurate with the scale required for high order combinatorial pooled perturbation screens (Aim 1). To analyze data generated with these methods, we will develop methods to: generate combinatorial genetic models from an under-sampled high-order combinatorial space, infer molecular mechanisms that explain the genetic models, and tackle the scale and noise of multiple types of single cell measurements (Aim 2). We will perform massive combinatorial perturbations and profiling to derive a genetic model of the transcriptional response to pathogens in dendritic cells, and then develop a dynamic molecular model that integrates the genetic model with high- resolution measurements of diverse molecular changes together with the RNA and protein life cycle (Aim 3). We will apply similar approaches to study cell fate transitions and maintenance in developing embryoid bodies, to build a combinatorial genetic model of how transcription and chromatin factors drive, stabilize or resist cell differentiation inan inherently heterogeneous population (Aim 4). Our studies will develop broadly-applicable methods for large-scale pooled combinatorial genetic perturbation with massive single cell genomic profiling of mammalian cells, and will generate the first genomic-scale quantitative combinatorial circuit models. We will share these approaches broadly with the community, enabling their application to diverse biological circuits.


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: 2023 ( Subtotal = -$24,254 )
2023	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	000	10	10/14/2022	NON-COMPETING CONTINUATION	-$24,254
														Subtotal = -$24,254

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	000	10	1/20/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $2,800,000 )
2020	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	001	10	9/25/2020	NON-COMPETING CONTINUATION	$0
2020	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	000	10	4/22/2020	NON-COMPETING CONTINUATION	$2,800,000
														Subtotal = $2,800,000

Issue Date FY: 2019 ( Subtotal = $2,800,000 )
2019	2019	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	000	9	6/12/2019	NON-COMPETING CONTINUATION	$2,800,000
														Subtotal = $2,800,000

Issue Date FY: 2018 ( Subtotal = $2,800,000 )
2018	2018	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	001	8	6/8/2018	NON-COMPETING CONTINUATION	$560,002
2018	2018	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	000	8	4/30/2018	NON-COMPETING CONTINUATION	$2,239,998
														Subtotal = $2,800,000

Issue Date FY: 2017 ( Subtotal = $2,800,719 )
2017	2017	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	001	7	5/31/2017	NON-COMPETING CONTINUATION	$2,800,000
2017	2016	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	000	6	3/13/2017	COMPETING CONTINUATION	$719
														Subtotal = $2,800,719

Issue Date FY: 2016 ( Subtotal = $3,700,000 )
2016	2016	BROAD INSTITUTE INC	7 CAMBRIDGE CENTER	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	000	6	5/24/2016	COMPETING CONTINUATION	$3,700,000
2016	2016	BROAD INSTITUTE INC	7 CAMBRIDGE CENTER	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	001	6	6/22/2016	COMPETING CONTINUATION	$0
														Subtotal = $3,700,000

Grand Total All Awards = $14,876,465

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Center for Cell Circuits

Award Number: RM1HG006193

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/09/2011

PERIOD OF PERFORMANCE END DATE: 04/30/2022

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer