# Thrombin mediated cytotoxicity during cerebral ischemia

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $110,246

## Abstract

We propose a novel and exciting hypothesis—based on literature and our own pilot data—that
neuronal injury stimulates astrocyte activation via thrombin and its receptor PAR-1, and the
resulting astrocyte response to injury yields transmissible paracrine protection of neurons.
Together, neurons, astroctyes, endothelial cells, pericytes, and oligodendroglia comprise the
neurovascular unit, or NVU. Data generated from the several aims will yield insights into the
mechanism for the well-documented phenomenon of pre-conditioning; will provide considerable
insights into the mechanisms of differential vulnerability to cerebral injury; and would likely yield
treatment options for stroke patients. To accomplish the aims, we are creating novel conditional
knock-out mice that will provide research tools to the broader research field. The previous
award, R01 NS075930, covered 8/15/2011 to 03/31/2015 and involved 4 aims. All proposed
work has been completed and published or under review. The data from our prior award has
already influenced stroke care significantly, in the form of two funded clinical trials. However, our
prior data could not fully explain the known differences among the elements of the NVU,
specifically, that astrocytes and endothelial cells tolerate ischemia better than neurons. What is
the mechanism of thrombin-mediated pre-conditioning, and can we relate that mechanism to
other forms of pre- and peri-conditioning? Why does the brain contain prothrombin mRNA and
protein and what purpose could be served by thrombin activation in brain? Could we derive
insights about the response of the brain to injury, and specifically explore the cell-subtype
interactions during injury among astrocytes, neurons, pericytes, oligodendroglia, and endothelial
cells? To answer these questions, and to address the central hypothesis of the present award
application, we added significant new models to our repertoire, and generated pilot data
speaking to the feasibility and novelty of the proposed new specific aims.

## Key facts

- **NIH application ID:** 9927678
- **Project number:** 5R01NS075930-09
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Patrick D Lyden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $110,246
- **Award type:** 5
- **Project period:** 2011-08-15 → 2020-09-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927678

## Citation

> US National Institutes of Health, RePORTER application 9927678, Thrombin mediated cytotoxicity during cerebral ischemia (5R01NS075930-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9927678. Licensed CC0.

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