# Modulating endothelial cell immunometabolism and mitochondrial morphologyimplications for organ transplantation

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $399,019

## Abstract

ABSTRACT: Organ transplantation is a mainstream therapy for patients with organ failure; however, despite
major advances in the field, there has been little progress regarding two major components of transplantation --
organ preservation and maintenance immunosuppression. Although essential, immunosuppressive therapy
carries a significant side-effect burden, often leading to patient death and graft failure. In addition, the process
of organ procurement most often includes use of grafts from brain dead donors followed by hypothermic
preservation of the organs in storage solutions. During these events, the endothelial cells (EC) in the organ
allografts are primed immunologically and are then subjected to the insults of reperfusion. This early injury
predisposes the EC to inappropriate antigen presentation and effects of chronic graft dysfunction, including graft
vasculopathy leading to long-term graft failure. Hypothermic preservation changes the metabolism of the
allograft, which in turn is hypothesized to alter the immunogenicity of the ECs ultimately affecting cellular
functional outcomes. Central to this cascade is the role of the mitochondria in shaping the immunometabolic
milieu of the allograft in the face of cold ischemia and reperfusion injury. In this proposal we, for the first time,
explore the mechanistic relationship between the mitochondrial morphology and immunometabolism of
ECs and their immunogenicity in the setting of transplantation. We build upon our own data to assess the
effects of forcing mitochondrial ultrastructural changes on the immunogenic profile of EC during the preservation
phase of transplantation. We propose that by dampening the early immunogenic effects of ECs, we can create
the opportunity to induce allograft tolerance with the use of reduced immunosuppressive regimens thereby
reducing the deleterious consequences of these necessary drugs. We will employ the scientific premise of
reprograming ECs to a more tolerogenic state by altering their metabolic core such that their ability to induce
proinflammatory changes from alloreactive T cells are diminished. Using clinically relevant in vivo models of
transplantation, we anticipate that altering EC mitochondria will improve graft survival and abrogate the pathology
associated with allograft rejection. Using our preliminary data as a backbone we hypothesize that cold ischemia
exacerbates the immunogenic capacity and metabolic profile of EC by altering mitochondrial morphology
resulting in allograft injury. Additionally, with the following aims, our goal will be to protect organ allografts and
skew the EC to a more tolerogenic phenotype.
 Aim 1. We will determine the impact of mitochondrial morphology during organ preservation on
the immunogenicity of endothelial cells in vitro.
 Aim 2. We aim to assess the impact of mitochondrial morphology on ischemia reperfusion injury
and acute transplant rejection in vivo.
Pre-treatment with mitochondrial fusion therapeutics will ...

## Key facts

- **NIH application ID:** 10402861
- **Project number:** 5R01AI142079-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** SATISH N NADIG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $399,019
- **Award type:** 5
- **Project period:** 2019-06-12 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402861

## Citation

> US National Institutes of Health, RePORTER application 10402861, Modulating endothelial cell immunometabolism and mitochondrial morphologyimplications for organ transplantation (5R01AI142079-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10402861. Licensed CC0.

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