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Transcriptional Co-Regulators in Epidermis

Award Number: R01AR044882
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/1998
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Transcriptional Co-Regulators in Epidermis - ABSTRACT Our long-term goal is to understand the transcriptional regulation of interfollicular epidermal (IFE) differentiation. The IFE is maintained by proliferating basal layer stem cells that self-renew, but also divide asymmetrically to generate postmitotic progeny deposited into the suprababasal compartment. As these progeny cells move toward the skin's surface they form successively the spinous, granular and cornified layers. The distinct morphology of each epidermal layer, combined with matching sharp boundaries in the expression of landmark genes, has established a stepwise differentiation model for the IFE. We have focused on the later IFE differentiation stages and their control by Grhl3, an evolutionarily conserved transcriptional regulator of epidermal barrier formation. Grhl3 also promotes keratinocyte migration where it activates a gene expression program distinct from that in differentiation. In this renewal application, we propose to employ emerging single cell approaches to define in vivo transcriptional regulation of IFE differentiation and collective keratinocyte migration- -at a scale and resolution not heretofore possible. In Aim 1, we will re-define IFE differentiation based on single cell RNA-seq (scRNA-seq) analysis. Our recent scRNA-seq experiments suggest that many gene batteries with distinct functions have expression patterns that cross different IFE layers, and that there is a large population of transition cells between the basal layer and the first spinous layer. Our hypothesis is that rather than a stepwise process, IFE differentiation is better understood as a continuous process where every cell in the IFE is at a distinct differentiation stage. We will use a new hybridization-based single cell method, to match our scRNA-seq data with landmarks in the IFE. We will also use ATAC-seq, to correlate chromatin accessibility with single cell mRNA expression. In Aim 2, we will understand how Grhl3 and other IFE regulators act in vivo. Unexpectedly, Grhl3 loss leads to an accumulation of an abnormal IFE cell population with progenitor characteristics. We will test the hypotheses that in addition to its well described role in activating terminal differentiation genes, Grhl3 suppresses the formation of this abnormal progenitor cell population. In Aim 3, we will define cellular heterogeneity in the migrating epithelial wound front. We will test the hypotheses that different regions of the migrating wound front contain groups of keratinocytes which can be classified based on their transcriptome and chromatin state; that there are cell signals within and between different keratinocyte populations of the wound front; that Grhl3 regulates adhesion properties of follower cells; and that cell heterogeneity, cell-cell signaling, and role of Grhl3 change as wound healing progresses. These experiments are significant and innovative because they will be the first to comprehensively characterize in an unbiased way the in vivo transcriptome heterogeneity of the IFE in differentiation and migration--relevant to many skin diseases. The premise is strong, based on extensive literature, published work on the role of Grhl3, and our recent scRNA-seq data.


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 = -$114 )
2025	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	25	4/2/2025	NON-COMPETING CONTINUATION	-$114
														Subtotal = -$114

Issue Date FY: 2023 ( Subtotal = $439,795 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	25	5/26/2023	NON-COMPETING CONTINUATION	$43,980
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	25	1/26/2023	NON-COMPETING CONTINUATION	$395,815
														Subtotal = $439,795

Issue Date FY: 2022 ( Subtotal = $435,396 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	24	1/25/2022	NON-COMPETING CONTINUATION	$395,814
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	24	5/11/2022	NON-COMPETING CONTINUATION	$39,582
														Subtotal = $435,396

Issue Date FY: 2021 ( Subtotal = $426,601 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	23	6/29/2021	NON-COMPETING CONTINUATION	$426,601
														Subtotal = $426,601

Issue Date FY: 2020 ( Subtotal = $439,795 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	22	3/30/2020	NON-COMPETING CONTINUATION	$43,981
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	22	2/10/2020	NON-COMPETING CONTINUATION	$395,814
														Subtotal = $439,795

Issue Date FY: 2019 ( Subtotal = $439,795 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	21	3/21/2019	COMPETING CONTINUATION	$439,795
2019	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	20	6/24/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $439,795

Issue Date FY: 2017 ( Subtotal = $319,048 )
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	20	6/14/2017	NON-COMPETING CONTINUATION	$31,905
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	3/27/2017	NON-COMPETING CONTINUATION	$287,143
														Subtotal = $319,048

Issue Date FY: 2016 ( Subtotal = $319,572 )
2016	2016	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	19	3/9/2016	EXTENSION WITH OR WITHOUT FUNDS	$319,572
														Subtotal = $319,572

Issue Date FY: 2015 ( Subtotal = $320,067 )
2015	2015	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	3/12/2015	NON-COMPETING CONTINUATION	$320,067
														Subtotal = $320,067

Issue Date FY: 2014 ( Subtotal = $320,286 )
2014	2014	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	6/20/2014	NON-COMPETING CONTINUATION	$320,286
														Subtotal = $320,286

Issue Date FY: 2013 ( Subtotal = $319,730 )
2013	2013	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	16	3/7/2013	COMPETING CONTINUATION	$319,730
2013	2011	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	3/5/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $319,730

Issue Date FY: 2011 ( Subtotal = $298,721 )
2011	2011	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	7/18/2011	NON-COMPETING CONTINUATION	$298,721
														Subtotal = $298,721

Issue Date FY: 2010 ( Subtotal = $312,086 )
2010	2010	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	7/20/2010	NON-COMPETING CONTINUATION	$312,086
														Subtotal = $312,086

Issue Date FY: 2009 ( Subtotal = $682,416 )
2009	2009	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Trans-NIH Recovery Act Research Support	000	12	7/10/2009	SUPPLEMENT FOR EXPANSION	$10,354
2009	2009	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	13	9/16/2009	SUPPLEMENT FOR EXPANSION	$146,526
2009	2009	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Trans-NIH Recovery Act Research Support	003	13	9/16/2009	SUPPLEMENT FOR EXPANSION	$209,477
2009	2009	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	13	7/10/2009	NON-COMPETING CONTINUATION	$316,059
														Subtotal = $682,416

Issue Date FY: 2008 ( Subtotal = $392,391 )
2008	2008	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	8/3/2008	NON-COMPETING CONTINUATION	$392,391
														Subtotal = $392,391

Issue Date FY: 2007 ( Subtotal = $369,767 )
2007	2007	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	4/11/2007	COMPETING CONTINUATION	$322,878
2007	2007	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	11	9/26/2007	SUPPLEMENT FOR EXPANSION	$46,889
														Subtotal = $369,767

Issue Date FY: 2006 ( Subtotal = $356,506 )
2006	2006	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	7/28/2006	NON-COMPETING CONTINUATION	$299,881
2006	2006	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	10	8/24/2006	SUPPLEMENT FOR EXPANSION	$56,625
														Subtotal = $356,506

Issue Date FY: 2005 ( Subtotal = $307,097 )
2005	2005	UNIVERSITY OF CALIFORNIA, IRVINE							Arthritis, Musculoskeletal and Skin Diseases Research	000	9	8/23/2005	NON-COMPETING CONTINUATION	$307,097
														Subtotal = $307,097

Issue Date FY: 2004 ( Subtotal = $393,259 )
2004	2004	UNIVERSITY OF CALIFORNIA, IRVINE							Arthritis, Musculoskeletal and Skin Diseases Research	001	8	8/31/2004	SUPPLEMENT FOR EXPANSION	$62,428
2004	2004	UNIVERSITY OF CALIFORNIA, IRVINE							Arthritis, Musculoskeletal and Skin Diseases Research	000	8	8/13/2004	NON-COMPETING CONTINUATION	$330,831
														Subtotal = $393,259

Grand Total All Awards = $8,108,522

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Transcriptional Co-Regulators in Epidermis

Award Number: R01AR044882

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/1998

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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