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Pre-Transplant Monocyte HDAC6 Expression and Risk of Primary Graft Dysfunction in Clinical Lung Transplant Recipients

Award Number: R01HL154241
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Primary Graft Dysfunction (PGD) remains a leading cause of early morbidity and mortality in lung transplant (Tx) recipients. The Lung Transplant Outcomes Group (LTOG) has been studying this problem for the past decade and a newly NIH-funded LTOG-related project (1U01HL14535-01), headed by Dr. Jason Christie (UPENN), involves long-term follow- up of adult lung transplant recipients. In preliminary studies, undertaken in collaboration with LTOG, we found that patients who subsequently developed PGD had significantly elevated pre-Tx levels of HDAC6 mRNA in their peripheral blood mononuclear cells. We identified CD14+ monocytes as the main source of upregulated HDAC6 in pre-Tx PGD-prone patients, observed an inflammatory phenotype of those monocytes after stimulation in vitro, and found that HDAC6 targeting significantly decreased cytokine production in an in vivo murine lung model of ischemia/reperfusion injury. Accordingly, we hypothesize that recipient blood monocytes with upregulated HDAC6 expression pre-lung Tx are important drivers of graft injury and development of PGD, and that such elevated HDAC6 expression in monocytes may be of prognostic and therapeutic significance. We propose to test this hypothesis by studying pre-Tx blood samples from patients enrolled in the parent U01 that began June 15, 2019. Aim 1: Determine if the phenotype of upregulated HDAC6 in monocytes of patients listed for lung Tx is a risk factor for developing PGD? We will expand upon our preliminary data using a larger sample size to evaluate 1.1) pre-Tx levels of monocyte HDAC6 expression, including mRNA and protein levels, and co-expression of classical markers of monocyte activation; and 1.2) post-Tx events (PGD with grade) in relation to the pre-Tx monocyte phenotype. Aim 2: What are the mechanisms by which HDAC6 alters key monocyte characteristics? We will: 2.1) evaluate cytokine expression (qPCR, flow cytometry, ELISA) by monocytes isolated from pre-Tx recipients and healthy donors, in relation to their HDAC6 levels; and 2.2) study how high HDAC6 expression regulates TLR/MyD88 pathway activation. Aim 3: Test whether HDAC6 inhibitor (HDAC6i) therapy can reverse or diminish the effects of monocyte dysfunction, including ex vivo and in a murine model of PGD. We will: 3.1) test effects of HDAC6i on monocyte activation, cytokine production and interaction with other immune cells; 3.2) test effects of one or more novel HDAC6i small molecules (monocyte specific HDAC6i, HDAC6 zinc-finger ubiquitin binding domain inhibitor and HDAC6i PROTAC); and 3.3) apply HDAC6i in vivo in a recently described new murine model of PGD. Importantly, our studies will • delineate pathogenic mechanisms of disease; • identify mechanisms or factors that influence and/or predict response to treatment; and • discover or validate biomarkers of disease development and/or progression.


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: 2024 ( Subtotal = $435,274 )
2024	2024	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	4	11/21/2023	NON-COMPETING CONTINUATION	$435,274
														Subtotal = $435,274

Issue Date FY: 2023 ( Subtotal = $435,361 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	001	3	2/11/2023	NON-COMPETING CONTINUATION	$43,536
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	3	12/3/2022	NON-COMPETING CONTINUATION	$391,825
														Subtotal = $435,361

Issue Date FY: 2022 ( Subtotal = $435,445 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	001	2	6/13/2022	NON-COMPETING CONTINUATION	$43,546
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	2	11/16/2021	NON-COMPETING CONTINUATION	$391,899
														Subtotal = $435,445

Issue Date FY: 2021 ( Subtotal = $454,430 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	1	12/11/2020	NEW	$408,987
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	001	1	6/11/2021	NEW	$45,443
														Subtotal = $454,430

Grand Total All Awards = $1,760,510

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Pre-Transplant Monocyte HDAC6 Expression and Risk of Primary Graft Dysfunction in Clinical Lung Transplant Recipients

Award Number: R01HL154241

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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