Triggering receptor expressed in Myeloid cells (TREM) Like transcript (TLT)-1 is a prominent platelet receptor stored in the ?-granules of platelets. While it is virtually absent on the surface resting platelets, it highly expressed on the surface of activated platelets and released as a soluble fragment (sTLT-1). TLT-1 binds to neutrophils and endothelial cells. During acute inflammation it mediates smooth leukocyte transmigration out of the vessels protecting the vessels from excessive bleeding. The effect is particularly prominent in the lungs. TLT-1 interaction with endothelial cells initiates cell growth and proliferation and when targeted in a Lewis lung carcinoma model displays anti-angiogenic properties. As such our studies have defined roles for TLT-1 in acute lung inflammation, atherosclerosis, and cancer. Here we propose to clinically translate our findings using the rich resource presented by the NIH biorepository. We will investigate samples from ARDS patients to find clinical correlation of TLT-1 positive microparticles with the mortality and hospital stay. We will evaluate samples from cardiovascular patients in the PEACE study for correlations of the soluble fragment and TLT-1 positive microparticles with adverse cardiac events..
Platelets are responsible for our vascular integrity. Platelet activation leads to the exposure of molecules stored within the ?-granules of platelets, including Trem-Like Transcript-1 or TLT-1. TLT-1 is responsible for mediating smooth neutrophil transmigration from the vessels and plays a protective role in lung biology. Cardiovascular disease (CVD) causes vascular dysfunction and platelet activation leading to the expression of TLT-1 and release of its soluble fragment (sTLT- 1). Here we propose to measure levels of TLT-1 in patients with Acute Respiratory Distress Syndrome (ARDS) to confirm our in vivo studies that suggest TLT-1 is protective during ARDS. Because CVD causes platelet activation and release of sTLT-1, we will measure sTLT-1 levels in plasma to verify, if it can be used as a biomarker for disease severity. Finally, because TLT-1 is hidden in the ?-granules and plays a role in lung hemostasis we will evaluate if patients suffering from transfusion induced lung injury have TLT-1 antibodies. This project will broaden our understanding of TLT-1 and platelet function in CVD, and ARDS.
