Thrombosis remains one of largest causes of mortality and morbidity in the western world. This study seeks to identify and understand key components involved with proper platelet function and subsequently to develop therapies to reduce the mortality associated with aberrant platelet function. There is an intimate relationship between inflammation and thrombosis. For example, inflammatory diseases, such as CVD and sepsis, cause aberrant platelet activation, leading to thrombosis and/or death. The mechanisms that control the liaison between inflammation and hemostasis are poorly defined, and thus this liaison remains a gap in our knowledge. It is known that platelets maintain vascular integrity at sites of inflammation, and consequently inflammatory diseases, such as CVD and sepsis, cause aberrant platelet activation often leading to death. P-selectin initiate's primary contact between platelets and leukocytes and/or endothelial cells and consequently, several clinical trials have been targeted at controlling inflammation via p-selectin, but success has been elusive. Early attempts to solve this challenge have focused on p-selectin interactions with ligands, rather than the potential for redundancy in function. This application represents a new approach to developing this promising target into treatment. We have cloned a platelet surface receptor called triggering receptor expressed in myeloid cells (TREM) like transcript-1, or TLT-1, that is found in mice and humans. TLT-1 is abundant, specific to platelets and megakaryocytes, and like p-selectin, stored in the platelet 1-granules. The soluble form of TLT-1 (sTLT-1) significantly enhances platelet aggregation and actin polymerization in platelets and endothelial cells; and Treml1 null mice show distinct phenotypic overlap with p- selectin null mice. The overlap includes: prolonged bleeding times, delayed neutrophil migration, higher basal neutrophil counts and hemorrhage in response to the Shwartzman model of vasculitis. These phenotypic similarities suggest that TLT-1 function complements that of p-selectin. We hypothesize that TLT-1 mediation of early cytoskeletal rearrangements complements p-selectin's function of initial adhesion of platelets to endothelial cells, and possibly leukocytes, thereby potentiating their ability to respond to both hematological and immunological cues. To test this hypothesis we have developed the following three specific aims.
AIM 1 : Define the mechanism by which sTLT-1 increases actin polymerization, AIM 2: Define the role of TLT-1 in inflammation and thrombosis.
AIM 3 : Develop the TLT-1/p-selectin (CD62P) double null mouse (DNTP) model. Our laboratory, having identified TLT-1and developed many TLT-1 reagents is the best suited to delineate TLT-1 function and to translate TLT-1's association with p-selectin from basic biology into clinical significance.

Public Health Relevance

Inflammatory diseases such as cardiovascular disease (CVD) and sepsis are major causes of death in the United States and the Western World; platelets play a large role in the control and survivorship of people suffering from these diseases. It is well established that the platelet receptor p-selectin mediates the connection between inflammation and thrombosis but success for this promising therapeutic target remains elusive. TREM like transcript-1 (TLT-1) is also a platelet receptor, with similar characteristics to p-selectin, which may play a role in p-selectin function; our project seeks to translate the basic science completed on p-selectin and TLT-1 into therapeutic means to aid the millions of people suffering from inflammatory diseases such as CVD or sepsis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090933-05
Application #
8828274
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Sarkar, Rita
Project Start
2011-06-16
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
5
Fiscal Year
2015
Total Cost
$259,414
Indirect Cost
$44,817
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
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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
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