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Mechanisms for GH action on epithelial cells

Award Number: R01DK113998
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
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: 03/31/2028

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Mechanisms for GH action on epithelial cells - PROJECT SUMMARY Accumulated damaged DNA, if left unrepaired, may disrupt tissue homeostasis, enabling a milieu favoring tissue degeneration, cancer, and metabolic dysfunction. DNA damage response and repair pathways are attenuated with aging and may also result in cell senescence, with senescence-associated secretory phenotype (SASP) promoting DNA damage and cell proliferation in neighboring cells, or in apoptosis. Non-pituitary growth hormone (npGH), synthesized locally in peripheral tissues, is recognized by the widely expressed GH receptor (GHR), and acts through autocrine/paracrine mechanisms. Our preliminary results show that npGH is induced by DNA damage in aged human colon tissues, in induced pluripotent stem cell (iPSC)-derived human colon 3D organoids, in hypophysectomized rat colon lacking endocrine GH, and in senescent colon cells. In turn, npGH suppresses DNA repair, further reinforcing DNA damage and resulting in chromosomal instability. We propose a novel hypothesis supporting the role of local epithelial GH as an adverse determinant of age-associated DNA damage accumulation and as a marker of epithelial aging. We will assess npGH induction and DNA damage in aged colon organoids, and Colon Intestine-Chip microfluidic devices. We will examine npGH expression in human colon tissue specimens derived from age- determined cohorts, assess spatial genomic profiles in conjunction with cells expressing npGH, and elucidate npGH as a cause of chromosomal instability. We will explore signaling mechanisms for npGH regulation of DNA damage response activity, senescence pathways, and DNA damage repair. Epithelial GHR signaling in vitro will be blocked with the GHR antagonist pegvisomant, a JAK2 inhibitor, and metformin. We will assess npGH actions in aged tissues derived from colon-specific and universal GHR knockout mice, and in GH overexpressing transgenic mice, and also assess npGH paracrine effects on colon epithelial somatic copy number alteration (sCNA) and respective genes affected by sCNA. We will study whether npGH is expressed in senescent cells, and whether it affects adjacent cell DNA damage and senescence. We will test paracrine npGH effects on senescence in Colon Intestine-Chip devices co-cultured with human colon fibroblast npGH transfectants, and will confirm in vitro results in transgenic models overexpressing GH or in GHR knockout mice. We largely focus on validated human colon epithelial models, yet experiments in this proposal are designed to elucidate a universal mechanism whereby local npGH reinforces epithelial age-associated DNA damage leading to tissue degeneration and or neoplasia.


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 = $367,400 )
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	4/29/2025	NON-COMPETING CONTINUATION	$367,400
														Subtotal = $367,400

Issue Date FY: 2024 ( Subtotal = $352,704 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	5/9/2024	NON-COMPETING CONTINUATION	$352,704
														Subtotal = $352,704

Issue Date FY: 2023 ( Subtotal = $367,400 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/24/2023	COMPETING CONTINUATION	$367,400
														Subtotal = $367,400

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/30/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $382,500 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/29/2021	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2020 ( Subtotal = $382,500 )
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/13/2020	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2019 ( Subtotal = $382,500 )
2019	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/14/2019	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2018 ( Subtotal = $383,625 )
2018	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/1/2018	NEW	$383,625
														Subtotal = $383,625

Grand Total All Awards = $2,618,629

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Mechanisms for GH action on epithelial cells

Award Number: R01DK113998

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

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: 03/31/2028

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