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Glycocalyx repair in sepsis using liposomal carriers of preassembled glycocalyx

Award Number: R01HL144528
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Glycocalyx repair in sepsis using liposomal carriers of preassembled glycocalyx - ABSTRACT Endothelial glycocalyx (EG), a carbohydrate-rich outermost surface layer, is a guardian of vascular functions. It is a sensor of the shear stress-activated endothelial nitric oxide production and flow-induced vasodilation, harbinger of growth factors, extracellular superoxide dismutase and anti-thrombin III, EG is a regulator of vascular permeability and leukocyte trafficking across the vascular wall, and it protects receptors from hyperstimulation by shielding them. EG is degraded in diverse cardiovascular, metabolic and renal diseases, thus leading to impairment of all the above functions. One of these conditions precipitating the loss of EG is septicemia, which is associated with high morbidity and mortality. We observed that mice with the polymicrobial sepsis exhibit a drastic reduction in the global volume of EG. Therefore, expeditious restoration of EG represents a rational pathogenetic therapy. We have recently designed, synthesized and tested in vitro, ex vivo and in vivo liposomal nanocarriers of preassembled glycocalyx. This pharmacological intervention improved mechanotransduction and nitric oxide synthesis, flow-induced vasodilation and renal microcirculation in endotoxemic mice. We have presently designed and synthesized the second generation of liposomal nanocarriers of preassembled glycocalyx featuring “stealth” liposomes with increased half-life, gold-label, as well as an array of possible modifications and demonstrated that they significantly improved survival of mice injected with the lethal dose of LPS. The present proposal is aimed at exploration of validity and efficacy of this pharmacologic approach in sepsis. We describe the steps to refine liposomal nanocarriers of preassembled glycocalyx, monitoring of the fate of these gold-labeled liposomes – their fusion with the plasma membrane, intracellular traffic, half-life in the vasculature. Thereafter we shall determine the effect of intravenous injection of liposomal nanocarriers on the course of sepsis and associated with it hemodynamic perturbations and the rate of functional restoration of affected organs. Proposed studies should not only refine this novel therapeutic tool but may also establish a pharmacologic approach to ameliorate sepsis-induced multiorgan failure.


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 = -$2,585 )
2025	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Blood Diseases and Resources Research	000	4	11/25/2024	NON-COMPETING CONTINUATION	-$2,585
														Subtotal = -$2,585

Issue Date FY: 2022 ( Subtotal = $541,200 )
2022	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Blood Diseases and Resources Research	000	4	7/1/2022	NON-COMPETING CONTINUATION	$541,200
														Subtotal = $541,200

Issue Date FY: 2021 ( Subtotal = $541,200 )
2021	2021	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Blood Diseases and Resources Research	000	3	6/14/2021	NON-COMPETING CONTINUATION	$541,200
														Subtotal = $541,200

Issue Date FY: 2020 ( Subtotal = $541,200 )
2020	2020	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Blood Diseases and Resources Research	000	2	7/16/2020	NON-COMPETING CONTINUATION	$541,200
														Subtotal = $541,200

Issue Date FY: 2019 ( Subtotal = $541,200 )
2019	2019	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Blood Diseases and Resources Research	000	1	8/5/2019	NEW	$541,200
														Subtotal = $541,200

Grand Total All Awards = $2,162,215

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Glycocalyx repair in sepsis using liposomal carriers of preassembled glycocalyx

Award Number: R01HL144528

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/05/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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