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The Evaluation of TLT-1 as treatment for ALI/ARDS

Award Number: F31HL136183
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/13/2017
PERIOD OF PERFORMANCE END DATE: 08/15/2018

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The Evaluation of TLT-1 as treatment for ALI/ARDS - Project Summary Acute Lung injury especially acute respiratory distress syndrome (ARDS) have been identified as life threatening conditions associated with significant mortality rate. Despite advances in the past decades in the knowledge on lung diseases, ARDS continues to claim the lives of more than 40% of its victims. The increase in health care associated costs has a major economic impact, while major clinical efforts to manage this disease are insufficient due to an uncomplete understanding of the mechanisms that control the pathology manifestations. Blood platelets, neutrophils and endothelial cells have been identified as the key components in the progression of ALI/ARDS. Moreover, our understanding of platelets function has shifted over the past years from a simple hemostatic tool to dynamic modulators of the immune response. The current paradigm of platelets intents to uncover the molecular mechanisms that make these cells major orchestrators of inflammation. Previous reports have demonstrated that the absence of platelets leads to increase endothelial damage, aberrant neutrophil function and hemorrhage during inflammation. Moreover, these effects have been shown to be controlled by the release of platelet granules during activation. To date, the identity of the platelet granule molecule or molecules involved in this remains to be elucidated representing gab in our knowledge. Accordingly, this study seeks to identify key platelet components that modulate systemic response during inflammation through the modulation of neutrophil-endothelial cell crosstalk and mechanisms involved. To dissect that question we will evaluate a platelet granule product known as TLT-1 in the mediation of the signaling mechanisms that modulates neutrophil -endothelial cell cross-talk during inflammation. The basis for the selection of TLT-1 as a potential target emerges from previous studies that demonstrated that TLT-1 knockout mice exhibited increased edema and hemorrhage together with a marked dysfunction of neutrophils during inflammation elicited by the Schwartzman reaction derived vasculitis. Moreover, we have evaluated TLT-1 functions in other models of inflammation including a mouse model of ALI using intranasal inoculation of LPS. Our preliminary data shows that TLT-1 prevents inflammatory associated hemorrhage while facilitate neutrophils transmigration in lung leading to decrease endothelial damage. Therefore, based on these previous observations we hypothesize that TLT-1 mediates the signaling mechanisms that regulate neutrophil capacity to transmigrate to the inflammatory site and modulate neutrophil- endothelial cell interactions during inflammation and therefore controlling the immune response. We developed two specific aims to answer that question. The aims are as follows: (i) Define a role for TLT-1 in platelet-neutrophill-endothelial cell interactions during inflammation and (ii) Elucidate the therapeutic effects of TLT-1 on ALI/ARDS. This two aims will help to fulfill our current understanding of platelet biological functions in inflammation. The answers obtained through the realization of this research work will empower our knowledge to be able to develop new alternative treatments directed to control systemic response to inflammation.


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: 2021 ( Subtotal = -$4,288 )
2021	2018	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Lung Diseases Research	000	2	12/18/2020	NON-COMPETING CONTINUATION	-$4,288
														Subtotal = -$4,288

Issue Date FY: 2019 ( Subtotal = -$11,270 )
2019	2018	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Lung Diseases Research	000	2	4/3/2019	NON-COMPETING CONTINUATION	-$11,270
														Subtotal = -$11,270

Issue Date FY: 2018 ( Subtotal = $30,184 )
2018	2018	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Lung Diseases Research	001	2	8/2/2018	NON-COMPETING CONTINUATION	$480
2018	2018	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Lung Diseases Research	000	2	1/12/2018	NON-COMPETING CONTINUATION	$29,704
														Subtotal = $30,184

Issue Date FY: 2017 ( Subtotal = $29,704 )
2017	2017	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Lung Diseases Research	000	1	1/13/2017	NEW	$29,236
2017	2017	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Lung Diseases Research	003	1	7/14/2017	NEW	$468
2017	2017	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Lung Diseases Research	002	1	2/23/2017	NEW	$0
2017	2017	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Lung Diseases Research	001	1	2/23/2017	NEW	$0
														Subtotal = $29,704

Grand Total All Awards = $44,330

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The Evaluation of TLT-1 as treatment for ALI/ARDS

Award Number: F31HL136183

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/13/2017

PERIOD OF PERFORMANCE END DATE: 08/15/2018

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