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Novel Molecular Target to Prevent Maturation Failure of Arteriovenous Fistula

Award Number: R01HL147662
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Novel Molecular Target to Prevent Maturation Failure of Arteriovenous Fistula - ABSTRACT Autologous arteriovenous fistula (AVF) is the preferred vascular access in hemodialysis. However, high rate of maturation failure due to inadequate blood flow in the outflow vein renders the fistula not useful for hemodialysis. Neointimal hyperplasia and failure of outward remodeling are the major causes of AVF maturation failure which is due to inflammation, proliferation, migration, and phenotypic changes of vascular smooth muscle cells (VSMCs), and extracellular remodeling due to increased matrix metalloproteinases (MMPs). We discovered increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1), TLR4 and related proteins in the immature AV fistula. Based on our novel findings, the central hypothesis is that hemodynamic injury during AVF creation induces inflammation to upregulate TREM-1 and TLR4 to enhance neointimal hyperplasia and vascular remodeling, and antagonizing TREM-1 and TLR4 will enhance AVF maturation. This hypothesis will be tested with the following Aims: Aim 1: Our corollary hypothesis predicts that the administration of TREM-1 and TLR4 antagonists will prevent maturation failure of AVF in swine. We will examine the effect of a potent inhibitory TREM-1 peptide in the AVF model in pigs. Since TREM-1 could synergize with TLR4 to mediate the pathology of AVF maturation failure, effect of a potent TLR4 antagonist will also be examined to prevent maturation failure of AVF. The outcome parameters will include neointimal hyperplasia in the inflow and outflow segments in the AVF, angiography of the AVF, color Doppler ultrasound, optical coherence tomography, and histology, immunostaining to analyze inflammation, expression of various mediators and infiltration of macrophages and neutrophils, VSMC apoptosis, and vascular remodeling. Aim 2: Our corollary hypothesis predicts that the TREM-1 and TLR4 antagonism inhibits inflammation and thus prevents maturation failure of AVF by reducing the development of intimal hyperplasia and vascular remodeling primarily due to inflammatory cells, cathepsin L, IL-8 and MMP-12. These studies will be performed in the blood and isolated VSMCs of femoral artery and femoral vein of the pigs from Aim 1. Mechanistic studies will examine the effect of TREM-1 and TLR4 inhibition in the presence of IL-8 on neutrophils, monocyte-differentiated macrophages and VSMCs, and cathepsin L-mediated elastin and collagen degradation in VSMCs, and the effect of elastin-derived peptides on monocyte differentiation into macrophages and VSMC proliferation and migration. Additional mechanistic studies will include the link between TLR4 and TREM-1 in promoting matrix remodeling, release of inflammatory cytokines from neutrophils and macrophages in the cross- talk inducing phenotype switch in VSMCs and macrophage polarization. The findings from this study will confirm if TREM-1 is a novel target for therapeutic intervention and extend the knowledge to develop better molecules to antagonize TREM-1 and design phase I clinical trials.


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	2022	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	7/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	6/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $704,979 )
2022	2022	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	7/15/2022	NON-COMPETING CONTINUATION	$704,979
														Subtotal = $704,979

Issue Date FY: 2021 ( Subtotal = $704,979 )
2021	2021	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	7/28/2021	NON-COMPETING CONTINUATION	$704,979
														Subtotal = $704,979

Issue Date FY: 2020 ( Subtotal = $704,979 )
2020	2020	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	7/21/2020	NON-COMPETING CONTINUATION	$704,979
														Subtotal = $704,979

Issue Date FY: 2019 ( Subtotal = $704,979 )
2019	2019	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	7/29/2019	NEW	$704,979
														Subtotal = $704,979

Grand Total All Awards = $2,819,916

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Novel Molecular Target to Prevent Maturation Failure of Arteriovenous Fistula

Award Number: R01HL147662

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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