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Regulation of Cell Turnover During Epithelial Tissue Homeostasis

Award Number: R01GM124043
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: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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Regulation of Cell Turnover During Epithelial Tissue Homeostasis - PROJECT SUMMARY ABSTRACT Cells within epithelial tissues are continually being eliminated by apoptosis and replaced by cell proliferation, however the mechanisms that coordinate cell removal with cell division to retain constant cell numbers remain unknown. Failure to coordinate the birth and death of cells can lead to dysregulation of population numbers and compromised barrier function, or conversely, tissue hyperplasia and carcinoma formation. Thus, a thorough understanding of the genetic underpinnings guiding cellular turnover in epithelial tissues will provide insight into molecular pathways that can be leveraged against diverse human pathologies by enhancing the removal and replacement of defective cells. The goal of this proposal is to define the cell and molecular mechanisms that regulate cell turnover in epithelial tissues to maintain appropriate overall population numbers. My recent results suggest that clearance of excess or defective cells was a major influence in whether neighboring cells would divide, extrude or die. Importantly, this work also suggested that alterations in the ability to rapidly clear apoptotic cells from the epithelial tissues may lead to several epithelial pathologies, including decreased barrier function in the intestinal epithelium or the accumulation of dangerous cells to promote carcinoma formation. Yet, a model system has been lacking to study how changes in apoptotic cell clearance could impact cell turnover and tissue maintenance in living epithelia. To investigate cell turnover in a living epithelial tissue, we have developed a toolset to perturb gene function and perform live imaging of division and death in the epithelia of the developing zebrafish, providing unparalleled access to analyze cell turnover in real time. Using the developing zebrafish to study cellular turnover in an epithelial bilayer, we have uncovered that induction of damage in a subset of basal epithelial cells promotes live cell neighbors to act as phagocytes that rapidly clear the apoptotic cellular debris. The basal stem cells then undergo division to compensate for the cell loss and maintain tissue integrity and function. Our preliminary data suggests that inhibition of either cell death or WNT signaling eliminates the apoptosis-induced division and results in failed regeneration. Further, genetic overexpression of WNT signaling in the context of a damage response led to an increase in overall cell numbers. In the following proposal, we will test the hypothesis that clearance of WNT-containing apoptotic cells by neighboring stem cells directly influences their proliferation to drive cell turnover in epithelia. In Aim 1, we will determine how removal of dying cells stimulates stem cell-mediated replacement. In Aim 2, we will define the molecular mechanisms guiding apoptosis-induced proliferation to maintain overall cell numbers. In Aim 3, we will determine if apoptotic bodies and microparticles can promote stem cell proliferation. Together, these studies will help reveal the cell and molecular events regulating epithelial tissue homeostasis and how alterations lead to human pathogenic conditions.


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 = -$8,338 )
2024	2022	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	5	1/13/2024	NON-COMPETING CONTINUATION	-$8,338
														Subtotal = -$8,338

Issue Date FY: 2022 ( Subtotal = $336,000 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	001	5	7/27/2022	NON-COMPETING CONTINUATION	$33,600
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	5	3/4/2022	NON-COMPETING CONTINUATION	$302,400
														Subtotal = $336,000

Issue Date FY: 2021 ( Subtotal = $358,914 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	4	3/10/2021	NON-COMPETING CONTINUATION	$358,914
														Subtotal = $358,914

Issue Date FY: 2020 ( Subtotal = $404,736 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	3	3/12/2020	NON-COMPETING CONTINUATION	$404,736
														Subtotal = $404,736

Issue Date FY: 2019 ( Subtotal = $381,822 )
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	2	3/5/2019	NON-COMPETING CONTINUATION	$336,000
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	001	2	7/25/2019	SUPPLEMENT FOR EXPANSION	$45,822
														Subtotal = $381,822

Issue Date FY: 2018 ( Subtotal = $535,972 )
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	001	1	9/20/2018	SUPPLEMENT FOR EXPANSION	$199,972
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	1	3/27/2018	NEW	$336,000
														Subtotal = $535,972

Grand Total All Awards = $2,009,106

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Regulation of Cell Turnover During Epithelial Tissue Homeostasis

Award Number: R01GM124043

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: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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