# Mechanisms of Endothelial Cell Dysfunction in Critically Ill Children

> **NIH NIH K08** · YALE UNIVERSITY · 2020 · $169,884

## Abstract

Project Summary
Candidate. I am an Instructor in pediatric critical care medicine at Yale School of Medicine and will be promoted
to Assistant Professor with academic promotion per Yale School of Medicine's Clinician Scholar track in July
2018. My K08 application will allow me to acquire additional mentored research experience so that I may become
an independent investigator with expertise in endothelial cell signaling and its disruption in critically ill children.
This research will build on my fellowship training that focused on the signals that regulate changes in vascular
permeability and their associated clinical consequences and will further develop my laboratory skills required to
successfully conduct vascular research, such as genetic modification of human cells, interrogation of intracellular
signaling pathways, and bioinformatic analysis. I will take graduate courses on vascular biology, bioinformatics,
and immunology research methods and will participate in national conferences. I have an outstanding mentor,
Dr. Jordan Pober, a world-class vascular biologist, along with advisors Dr. Mustafa Khokha, expert in genetics,
and Dr. Vince Faustino, expert biostatistician and clinical trialist. This multidisciplinary mentorship team, along
with the resources available through the VBT program at Yale, will allow me to develop the necessary skills to
function as an extramurally funded clinician scientist focused on improving the care of critically ill children.
Research Project. Endothelial cells (ECs) actively regulate vessel permeability that is essential for organ
function and patient survival. During cardiopulmonary failure, loss of EC permselectivity results in capillary leak
that contributes to morbidity and mortality in children. The unique regulation of the signaling events that produce
permeability changes in capillary EC is largely unknown. Likewise, how critical illness induces EC dysfunction
remains unknown, due in large part to our inability to directly assess EC changes in critically ill patients. I recently
demonstrated the importance of the regulation of the small GTPase RhoB in a pediatric patient with systemic
capillary leak syndrome caused by a single gene mutation. In Aim 1, I test the hypothesis that pathological
capillary permeability is regulated by small GTPases and that these pathways are influenced by transcriptional
changes induced by inflammatory cytokines. I will interrogate intracellular signaling pathways in capillary ECs
cultured from different organs (skin and lung) to determine the effect of their modulation on trans-endothelial
electrical resistance. In Aim 2, I will test the hypothesis that ECs undergo transcriptional changes in response to
critical illness. I will analyze the entire transcriptome of individual venous ECs collected directly from critically ill
children using single cell RNA sequencing. I will assess the functions of identified candidate gene products using
pharmacologic, genetic, and immunolog...

## Key facts

- **NIH application ID:** 9852340
- **Project number:** 5K08HL136898-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** RICHARD W PIERCE
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,884
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852340

## Citation

> US National Institutes of Health, RePORTER application 9852340, Mechanisms of Endothelial Cell Dysfunction in Critically Ill Children (5K08HL136898-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852340. Licensed CC0.

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