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ZIP8-dependent Zinc Metabolic Regulation in Alveolar Progenitor Cell Aging and Fibrosis

Award Number: R01AG078655
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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ZIP8-dependent Zinc Metabolic Regulation in Alveolar Progenitor Cell Aging and Fibrosis - Abstract With the rapid growth of an aging population worldwide, the annual incidences of aging-associated lung diseases such as idiopathic pulmonary fibrosis (IPF), are increasing. Therefore, there is a great need to comprehensively investigate the complex process of lung aging and develop interventions to extend the health span of the elderly population. Type 2 alveolar epithelial cells (AEC2s) function as progenitor cells that maintain epithelium homeostasis and repair the lung after injury. A characteristic of the aging lung is progenitor cell exhaustion and, in turn, impairs alveolar regeneration. Persistent epithelial cell injury coupled with inadequate alveolar epithelial repair due to progenitor cell failure results in a prototype of age-associated lung disease, IPF. In fact, it has been argued that IPF is a disease of premature aging of AEC2s. Hence, studies focusing on re-activating and/or expanding AEC2 progenitor cells in lung aging are needed. As we reported, AEC2 progenitor cells are exhausted in human IPF lungs. IPF AEC2s fail to regenerate in organoid assays relative to normal AEC2s. In our preliminary studies for this application, we found a decrease in AEC2 renewal capacity and a loss of AEC2 population occur during lung aging. We aimed to uncover the molecular mechanisms that contribute to impaired AEC2 renewal during aging, with the long-term goal of pointing the way to novel interventions that can rejuvenate aged AEC2s. We have found that: 1) The renewal capacity of AEC2s in 18-20 months old aged mouse lungs are reduced just as what we observed with IPF lungs; 2) Using single cell RNA-seq and flow cytometry, we identified a deficiency of a specific zinc transporter SLC39A8 (encoding ZIP8) in AEC2s from 18-20 months old aged mouse lungs and IPF lungs; 3) Sirtuin signaling pathway was downregulated in AEC2s from bleomycin-injured old mouse lungs and IPF lungs; 4) ZIP8 regulates AEC2 progenitor function through SIRT1 and ZIP8/SIRT1 axis is required for AEC2 renewal. In addition, we have generated a novel mouse model of Zip8 deficiency in AEC2 cells that reveals phenotypes of premature AEC2 aging. Based on these novel findings, we hypothesize that ZIP8 deficiency occurs in AEC2s with aging and downregulates SIRT1, thereby impairing AEC2 progenitor cell renewal. Furthermore, we propose that restoring critical components of the ZIP8/zinc/SIRT1 pathway will improve AEC2 progenitor activity and, thus maintain lung epithelial integrity and prevent age-associated lung diseases.


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 = $533,653 )
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Aging Research	001	4	6/10/2025	NON-COMPETING CONTINUATION	$43,562
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Aging Research	000	4	3/19/2025	NON-COMPETING CONTINUATION	$490,091
														Subtotal = $533,653

Issue Date FY: 2024 ( Subtotal = $544,545 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Aging Research	000	3	5/2/2024	NON-COMPETING CONTINUATION	$544,545
														Subtotal = $544,545

Issue Date FY: 2023 ( Subtotal = $544,545 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Aging Research	000	2	5/12/2023	NON-COMPETING CONTINUATION	$544,545
														Subtotal = $544,545

Issue Date FY: 2022 ( Subtotal = $544,545 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Aging Research	000	1	7/27/2022	NEW	$544,545
														Subtotal = $544,545

Grand Total All Awards = $2,167,288

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ZIP8-dependent Zinc Metabolic Regulation in Alveolar Progenitor Cell Aging and Fibrosis

Award Number: R01AG078655

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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