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The Role of HuR in HIV related COPD

Award Number: R01HL162590
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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The Role of HuR in HIV related COPD - Summary: Both retrospective and longitudinal cohort analyses strongly associate HIV infection with the premature initiation and progression of chronic obstructive pulmonary disease (COPD). Improving long-term pulmonary outcomes and longevity in people living with HIV (PLWH) will require a better understanding of how cigarette smoke accelerates COPD in this patient population. We know that exposure to cigarette smoke causes proliferative and oxidative responses in airway epithelial cells that promote HIV-related COPD. Our prior studies showed that the HIV protein Tat and chronic smoke exposure both reduced lung levels of the RNA binding protein human antigen R (HuR), which regulates the balance between decay and translation of multiple mRNA targets. Similarly, we determined that prolonged smoke exposure reduces HuR levels in primary human airway epithelial cells (HAECs) isolated from COPD subjects and in lung tissue sections from COPD airways. The loss of HuR is important since we found that chronic smoke exposure worsened airflow obstruction in airway specific HuR knockout mice. Moreover, our RNA-seq studies discovered that knocking down HuR in HAECs dysregulates cell proliferation and reduces antioxidant gene expression. Another line of evidence indicates that the proto- oncogene tyrosine-protein kinase c-Src negatively regulates HuR expression. We identified enhanced c-Src activation in HAECs from COPD subjects and in the lungs of EcoHIV infected mice. Thus, we hypothesize that chronic smoke exposure and HIV induce c-Src to down regulate HuR and thereby impair airway epithelial repair mechanisms in COPD. This loss of HuR alters the airway transcriptome to promote airflow obstruction in PLWH. We will test the hypothesis in three aims: Aim 1: We will use transcriptomic analysis to determine how HIV and cigarette smoke induce COPD by altering gene expression in human airway epithelial cells from healthy, COPD and HIV/COPD subjects Aim 2. We will employ in vivo HIV COPD models to ascertain how HuR in the airway epithelium counters the oxidative damage that promotes airway injury and airflow obstruction in HIV. Aim 3. We will employ in vitro and in vivo HIV COPD models to determine how c-Src regulates HuR to alter oxidative and proliferative responses that promote airway injury and airflow obstruction in HIV. These studies will set the stage for novel pharmacologic interventions that restore HuR expression to counter the airway epithelial injury that impairs lung function and tissue integrity in HIV infected COPD subjects.


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 = $705,023 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	000	4	6/13/2025	NON-COMPETING CONTINUATION	$705,023
														Subtotal = $705,023

Issue Date FY: 2024 ( Subtotal = $708,757 )
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	000	3	6/13/2024	NON-COMPETING CONTINUATION	$708,757
														Subtotal = $708,757

Issue Date FY: 2023 ( Subtotal = $724,234 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	000	2	6/14/2023	NON-COMPETING CONTINUATION	$724,234
														Subtotal = $724,234

Issue Date FY: 2022 ( Subtotal = $763,296 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	000	1	8/31/2022	NEW	$763,296
														Subtotal = $763,296

Grand Total All Awards = $2,901,310

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The Role of HuR in HIV related COPD

Award Number: R01HL162590

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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