Monday, March 10, 2025 3/10/2025

The impact of aged-related dermal microenvironment on the development of precancerous stroma and cancer initiation

Award Number: U01AG077924
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Cancer is clearly a disease of aging. This connection between aging and cancer incidence is especially true in the case of skin cancer, which is the most common form of human cancer, accounting for more than all other cancers combined in USA. The major objective of this application is to gain understanding of cellular and molecular mechanisms that link age-related skin changes to the initiation of skin cancer. This application is based on our findings that fibroblasts in aged human skin express elevated levels of a matricellular protein named CCN1, and that elevated CCN1 acts to deleteriously alter the dermal compartment of skin to create a microenvironment that enhances cancer initiation. Based on these observations, we have created genetically modified mice that express elevated levels of CCN1 selectively in dermal fibroblasts (source of elevated CCN1 in aged human skin). These mice exhibit strikingly accelerated dermal aging and display multiple hallmarks of aging that are seen in human skin. Importantly, mice that express elevated levels of CCN1 in the dermis also have a high propensity for skin tumor initiation. These results provide direct support for the overarching hypothesis of this application; that age- related changes in the dermal microenvironment, driven by fibroblast expression of CCN1, create a dermal microenvironment that enhances initiation of keratinocyte cancer. We propose to test this hypothesis with the following specific aims. Aim 1: define the impact of CCN1-induced accelerated dermal aging on keratinocyte cancer initiation. Aim 2: test the hypothesis that activation of the hepatocyte growth factor pathway by the CCN1-induced dermal aging microenvironment drives keratinocyte cancer initiation. Aim 3: using targeted gene deletion, test the requirement for CCN1 expression in dermal fibroblasts for the development of an aging-related dermal microenvironment and initiation of keratinocyte cancer. The aims of this proposal directly address the objectives of the National Cancer Institute/National Aging Institute Funding Opportunity Announcement to understand mechanisms by which age-related alterations in the cellular niche/microenvironment contribute to cancer initiation.


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 = $0 )
2025	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	4	3/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $576,705 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	001	4	4/26/2024	NON-COMPETING CONTINUATION	$421,997
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	002	4	8/23/2024	SUPPLEMENT FOR EXPANSION	$154,708
2024	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	3	3/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $576,705

Issue Date FY: 2023 ( Subtotal = $428,635 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	3	7/25/2023	NON-COMPETING CONTINUATION	$428,635
														Subtotal = $428,635

Issue Date FY: 2022 ( Subtotal = $435,078 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	2	7/5/2022	NON-COMPETING CONTINUATION	$435,078
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	001	2	8/25/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $435,078

Issue Date FY: 2021 ( Subtotal = $455,335 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	1	9/17/2021	NEW	$455,335
														Subtotal = $455,335

Grand Total All Awards = $1,895,753

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The impact of aged-related dermal microenvironment on the development of precancerous stroma and cancer initiation

Award Number: U01AG077924

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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