According to the World Health Organization, Cardiovascular disease (CVD) is responsible for 31% of deaths worldwide making it the largest global cause of mortality. These numbers are reflected in the United states where over 600,000 people died of CVD. CVD is an inflammatory disease that often leads to mortality by thrombosis and platelets mediate both the inflammatory and thrombotic aspects of CVD. Our laboratory studies the Triggering receptor expressed in myeloid cells or (TLT-1) that is stored in the ??granules of the platelets and is both expressed to the platelet surface and released after platelet activation. TLT-1 binds fibrinogen. While TLT-1 has demonstrated roles in Cardiovascular disease, sepsis, and acute lung injury, its interaction with fibrinogen is poorly understood. We hypothesize that TLT-1?s interaction with fibrinogen is a major pathway by which the immune system commandeers the hemostatic system for immune function. In this application we propose to mechanistically define this interaction and demonstrate is usefulness as a therapeutic target. We propose the following three aims:
Aim I ? Determine the relative contribution of fibrinogen binding to TLT-1 and ?IIb?2 using double deficient (treml1-/-/itga2b-/-) mice;
Aim II - Elucidate TLT-1 signaling pathways;
Aim III ? Evaluate the effect of TLT-1 prophylactics on the progression of CVD and obesity. At the completion of these aims we will have defined TLT-1?s contribution to platelet interaction with fibrinogen and is potential as a therapeutic target.

Public Health Relevance

Cardiovascular disease (CVD) is the largest cause of mortality and morbidity in the United State and worldwide. Platelets through their interaction with fibrinogen are critical to the progression of CVD. The current paradigm of platelet aggregation is that fibrinogen interacts with ?IIb?3 to mediate the platelet clot. We have identified a platelet protein, called TREM Like transcript (TLT-1), that binds fibrinogen and mediates inflammatory aspects of platelet/fibrinogen interactions. However, this interaction remains poorly understood. Here we will define those interactions with the goal of developing novel treatments for CVD

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090933-07
Application #
9996765
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sarkar, Rita
Project Start
2011-06-16
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Puerto Rico Rio Piedras
Department
Type
Schools of Arts and Sciences
DUNS #
143960193
City
San Juan
State
PR
Country
United States
Zip Code
00931
Morales-Ortíz, Jessica; Rondina, Matthew T; Brown, Samuel M et al. (2018) High Levels of Soluble Triggering Receptor Expressed on Myeloid Cells-Like Transcript (TLT)-1 Are Associated With Acute Respiratory Distress Syndrome. Clin Appl Thromb Hemost 24:1122-1127
Morales-Ortíz, Jessica; Deal, Victoria; Reyes, Fiorella et al. (2018) Platelet-derived TLT-1 is a prognostic indicator in ALI/ARDS and prevents tissue damage in the lungs in a mouse model. Blood 132:2495-2505
Kucheryavykh, Lilia Y; Dávila-Rodríguez, Josué; Rivera-Aponte, David E et al. (2017) Platelets are responsible for the accumulation of ?-amyloid in blood clots inside and around blood vessels in mouse brain after thrombosis. Brain Res Bull 128:98-105
Esponda, Omar L; Hunter, Robert; Del Río, José R Rivera et al. (2015) Levels of soluble TREM-like transcript 1 in patients presenting to the emergency department with chest pain. Clin Appl Thromb Hemost 21:30-4
Castillo-Pichardo, Linette; Humphries-Bickley, Tessa; De La Parra, Columba et al. (2014) The Rac Inhibitor EHop-016 Inhibits Mammary Tumor Growth and Metastasis in a Nude Mouse Model. Transl Oncol 7:546-55
Ramos, Gladiany; Loperena, Yaliz; Ortiz, Giovanni et al. (2014) The addition of a pregnenolone pendant group enhances the anticancer properties of titanocene dichloride in a mcf-7 xenograft model. Anticancer Res 34:1609-15
Ferrer-Acosta, Yancy; González, Marieli; Fernández, Mónica et al. (2014) Emerging Roles for Platelets in Inflammation and Disease. J Infect Dis Ther 2: