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Stress Pathways in the Induction of Metaplasia

Award Number: F31CA236506
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2018
PERIOD OF PERFORMANCE END DATE: 09/25/2020

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Stress Pathways in the Induction of Metaplasia - PROJECT SUMMARY Stress Pathways in the Induction of Metaplasia Mature cells in many organ systems can undergo a reprogramming event in which cells dedifferentiate, convert to a progenitor-like state, and enter the cell cycle in response to tissue injury. This cell state change results in the formation of metaplasia to repair lost and damaged tissue. If tissue is unable to return to normal after metaplasia formation this is a risk factor for cancer formation, as is the case with spasmolytic polypeptide- expressing metaplasia in the stomach and acinar-to-ductal metaplasia in the pancreas. The cellular and molecular mechanisms that govern injury-induced metaplasia formation are largely undescribed, yet they appear to occur in a consistent, step-wise manner: 1. Autodegradation of differentiated proteins, 2. Expression of a progenitor/metaplastic gene network, and 3. Entry to the cell cycle. A recent publication from our lab demonstrated that these steps are conserved in mouse injury models in the stomach, pancreas, liver, and kidneys. The experiments presented in this proposal aim to interrogate the importance of two proteins known to be involved in the integrated stress response, eukaryotic initiation factor 2 (eIF2) and activating transcription factor 3 (ATF3), during the development of metaplasia. Preliminary results show that eIF2 becomes inactivated rapidly after injury in mouse models that induce pancreatic and gastric metaplasia. ATF3 protein and Atf3 mRNA also rapidly increase in these injury models concurrent with eIF2 inactivation. The Aims presented here will further determine if Atf3 function and eIF2 inactivation are necessary components of metaplasia initiation with detailed mechanistic studies using Atf3-null mice, pharmacological inhibitors of eIF2, and an injury model in Caco-2 cell lines. Experiments will also determine how eIF2 becomes inactivated in this injury response and identify genes differentially expressed by ATF3. If the experiments presented here support the hypothesis that eIF2 and ATF3 are critical for mature cell reprogramming following injury, future studies will determine the importance of eIF2 and ATF3 in human gastric and pancreatic metaplasia and adenocarcinoma.


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 = -$1,747 )
2023	2020	REDACTED DUE TO PII		SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Research Manpower	000	2	10/17/2022	NON-COMPETING CONTINUATION	-$1,747
														Subtotal = -$1,747

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	REDACTED DUE TO PII		SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	001	2	4/22/2022	NON-COMPETING CONTINUATION	-$3,815
2022	2020	REDACTED DUE TO PII		SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	002	2	9/29/2022	NON-COMPETING CONTINUATION	$3,815
2022	2019	REDACTED DUE TO PII		SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	000	1	4/22/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = -$4,571 )
2021	2020	REDACTED DUE TO PII		SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	000	2	10/30/2020	NON-COMPETING CONTINUATION	-$4,571
														Subtotal = -$4,571

Issue Date FY: 2020 ( Subtotal = $31,438 )
2020	2020	REDACTED DUE TO PII		SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	001	2	2/13/2020	NON-COMPETING CONTINUATION	$504
2020	2020	REDACTED DUE TO PII		SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	000	2	11/13/2019	NON-COMPETING CONTINUATION	$30,934
														Subtotal = $31,438

Issue Date FY: 2019 ( Subtotal = $30,934 )
2019	2019	REDACTED DUE TO PII		SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	000	1	11/29/2018	NEW	$30,934
2019	2019	REDACTED DUE TO PII		SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	001	1	11/29/2018	NEW	$0
														Subtotal = $30,934

Grand Total All Awards = $56,054

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Stress Pathways in the Induction of Metaplasia

Award Number: F31CA236506

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2018

PERIOD OF PERFORMANCE END DATE: 09/25/2020

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