# Tie2-driven vascular control in critical illness

> **NIH NIH R35** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $921,078

## Abstract

PROJECT SUMMARY
Sepsis affects millions of Americans annually and is a leading cause for intensive care utilization. Currently no
therapies exist to target the abnormal host response that is widely acknowledged to contribute to multi-organ
dysfunction and death from severe infection. The applicant has received continuous R01 support from the
NHLBI since 2007-2008 to research the host vascular response in sepsis. Our group has identified the Tie2
receptor and its ligands, the Angiopoietins, as an important switch in the endothelium that may govern
essential elements of the vascular response to sepsis. We have proposed that Angiopoietin-2, an antagonist
of Tie2 that is induced during sepsis, potentiates vascular leakage and thereby contributes to acute respiratory
distress arising from sepsis and related conditions. Since Angiopoietin-2 can be measured peripherally, we
have also proposed that its circulating concentration may predict the risk of adverse outcomes from sepsis and
may enable clinicians to track the host vascular response in a quantitative and operator-independent fashion.
Finally, we have recently found evidence that polymorphisms at the TIE2 locus itself may inform the level of
gene expression, and in turn, how well or poorly an individual's blood vessels respond to the stress of sepsis.
This body of work to which we and many others have now contributed suggests that we are on the cusp of
developing breakthrough personalized medicine approaches based on the host vascular response in sepsis.
Such advances could revolutionize the care delivered in our ICUs.
This application seeks to develop the core hypothesis that the Tie2 axis may be a crucial determinant of the
host vascular response in sepsis through the following three themes: (1) create humanized mouse models of
the Tie2 axis using cutting-edge genome engineering to model the human host vascular response, and its
genetic determinants, in a physiological context; (2) identify major mechanisms by which Tie2 and the
endothelium regulate hemostasis in sepsis; and (3) study the crosstalk between the microcirculation and
metabolically active organs to understand how the host vascular response and dysmetabolism collaborate to
drive multi-organ dysfunction.
The outstanding qualifications of our team in the Tie2 field, genetic epidemiology, thrombosis research, and
metabolism uniquely position us to deliver an unprecedented and integrated molecular view of sepsis from the
perspective of blood vessels that is not only highly responsive to the challenges in sepsis research identified by
global leaders, but could fundamentally alter paradigms of patient care in the ICU.

## Key facts

- **NIH application ID:** 9843726
- **Project number:** 5R35HL139424-03
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Samir M Parikh
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $921,078
- **Award type:** 5
- **Project period:** 2018-01-16 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843726

## Citation

> US National Institutes of Health, RePORTER application 9843726, Tie2-driven vascular control in critical illness (5R35HL139424-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9843726. Licensed CC0.

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