# Pre-exposure Immunologic Health and Linkages to SARS-COV2 Serologic Responses, Endothelial Cell Resilience, and Cardiovascular Complications: Defining the mechanistic basis of high risk endotypes.

> **NIH NIH U01** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $673,696

## Abstract

Abstract
The objective of this proposal is to understand the immunologic foundations of heart disease which can occur
as a result of COVID19. Cardiac impairment, when it develops is often fatal, and our hypothesis is that the
maintenance of endothelial function is critical to surviving the protracted nature of COVID19 pneumonia,
especially in those with reduced or delayed antibody responses.
 Our first aim will be to analyze those differences in immune function which pre-date infection but appear
to impact the risk of fatal COVID. This will be done by enrolling those at high risk for developing COVID19
(frontline healthcare workers), and performing serially assessments of their immunologic function if they develop
COVID. We will specifically investigate the mechanisms that link pre-infection inflammatory pathways to
protective serologic responses and symptom severity and recovery.
 Our second aim will be to perform in vitro experiments to assess the requirements for endothelial cell
dysfunction and infectivity. We will compare various inflammatory and cardiovascular stimuli which seem to play
a role in promoting COVID19-related cardiovascular complications.
 Our third aim is to characterize immune cells, endothelial cells, and cardiomyocytes in heart tissue from
those with COVID19-induced left ventricular dysfunction. Using single cell sequencing techniques, we will
determine cellular and molecular signatures that characterize the microenvironment of the COVID19-affected
heart, compared to appropriate controls.
 Our conceptual model is that pre-existing immune dysfunction 1) reduces the efficiency of neutralizing
antibody responses, and 2) in conjunction with cardiovascular disease risk factors, induces endothelial
downregulation/depletion of nodal regulators which protect against inflammatory insults. This renders
endothelial cells unable to withstand COVID-specific stimuli. Once completed, this study will provide the
necessary information to improve the identification of those at risk for COVID-related heart disease and develop
rationale approaches to improve the improve survival in the setting of COVID.

## Key facts

- **NIH application ID:** 10680625
- **Project number:** 4U01CA260513-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Timothy An-thy Chan
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $673,696
- **Award type:** 4N
- **Project period:** 2020-09-30 → 2025-03-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10680625

## Citation

> US National Institutes of Health, RePORTER application 10680625, Pre-exposure Immunologic Health and Linkages to SARS-COV2 Serologic Responses, Endothelial Cell Resilience, and Cardiovascular Complications: Defining the mechanistic basis of high risk endotypes. (4U01CA260513-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10680625. Licensed CC0.

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