# Membrane Phospholipids: The Key Regulators of Tissue Factor Encryption/Decryption

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH CTR AT TYLER · 2020 · $457,033

## Abstract

Upon vascular injury, plasma clotting factor VII (FVII) along with traces of activated FVII (FVIIa) come into
contact with the cofactor tissue factor (TF), which is expressed constitutively in cells within the vessel wall.
Complex formation of FVIIa with TF results in a marked enhancement of the catalytic activity of FVIIa and
triggers TF-mediated blood coagulation. Certain disease conditions induce TF expression in circulating blood
cells and vascular endothelial cells and thus allow direct contact between circulating blood and TF that leads
to thrombosis. While TF-mediated blood coagulation is essential to maintain hemostasis, the aberrant
activation of TF-mediated blood coagulation leads to thrombosis, the precipitating event in acute myocardial
infarction, ischemic stroke, and sepsis. Therefore, the proper regulation of TF expression and the activity is
critical for not only to the maintenance of the hemostatic balance but also for health in general. Typically, most
of the TF expressed in cells stays encrypted with very little procoagulant activity that is sufficient to achieve
hemostasis but not to cause intravascular coagulation. Cellular injury enhances TF procoagulant activity
greatly without altering TF antigen levels, i.e., transforming cryptic TF to prothrombotic TF. TF procoagulant
activity in cells is controlled dynamically by a variety of post-translational mechanisms. Our recent studies
revealed that sphingomyelin (SM) in the outer leaflet of the plasma membrane is responsible for maintaining
TF in an encrypted state and that hydrolysis of SM activates TF and releases TF+ microvesicles (MVs). SM
metabolism is altered in many disease settings, including atherosclerosis, diabetes, sepsis, and cancer, the
same disease settings that induce aberrant activation of TF. The current proposal is built on the above novel
findings and proposes to investigate the pathophysiologic relevance of SM metabolism in regulation of TF-
mediated hemostasis, thrombosis, and inflammation. Aim 1 focuses on elucidating mechanisms by which SM
metabolism regulates TF procoagulant activity, whereas Aim 2 investigates whether SM metabolism
influences hemostasis and thrombosis. Experiments proposed in Aim 3 will test the hypothesis that acute
inflammation-induced alterations in SM metabolism play a key role in TF activation and TF-mediated
coagulopathy. Aim 4 focuses on investigating whether altered SM metabolism contributes to inflammation via
the regulation of TF activity. In the proposed studies, we will manipulate SM levels in macrophages,
endothelial cells, and other cell types by the overexpression or down regulation of various enzymes involved
in the SM metabolism or using specific pharmacological inhibitors of these enzymes. We will employ various
knock-out mice with altered SM metabolism and murine models of hemostasis and thrombosis to investigate
the pathophysiologic relevance of the newly identified mechanism. Our proposed studies will lead to a
parad...

## Key facts

- **NIH application ID:** 9968901
- **Project number:** 2R01HL124055-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH CTR AT TYLER
- **Principal Investigator:** Vijaya Mohan Rao Lella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $457,033
- **Award type:** 2
- **Project period:** 2015-09-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968901

## Citation

> US National Institutes of Health, RePORTER application 9968901, Membrane Phospholipids: The Key Regulators of Tissue Factor Encryption/Decryption (2R01HL124055-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9968901. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*