# Improving transplant organ survival through the mitigation of donor-derived mitochondrial damage-associated molecular patterns

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $407,613

## Abstract

The need for transplantation vastly exceeds organ availability, and many of the over 30,000 solid organ
transplants (grafts) performed in the United States annually will be lost within 5 years —primarily as a result of
immune-mediated graft rejection. Thus, there is a critical need for improved approaches to reduce graft
rejection and to expand the pool of usable organs. A novel strategy for reducing rejection and improving graft
quality is to mitigate graft injury occurring prior to transplantation. The majority of transplant organs are from
deceased donors, which have inferior outcomes when compared to organs from living donors. This difference
is believed to be a result of increased graft injury and immunogenicity caused by inflammation resulting from
brain death. The rationale for the proposed research is that identifying the specific cellular and molecular
pathways that promote graft rejection in deceased organ donors will lead to the development of novel
approaches to improve organ quality prior to transplant. It is now known that mitochondria released into the
circulation after brain death are potent stimulators of sterile inflammation and promote graft dysfunction and
rejection. The overall objectives of this proposal are to define the specific mitochondria-derived damage
associated molecular patterns (mtDAMPs) that cause graft injury, and to develop methods to mitigate
mtDAMP-induced inflammation in order to improve graft quality prior to transplantation. The central hypothesis
is that the function and survival of transplanted organs can be improved by reducing graft inflammation and
injury caused by circulating mitochondria in deceased donors. Guided by strong preliminary data, and using a
combination of animal models and human tissues, the hypothesis will be tested through completion of three
Specific Aims: 1) Identify the mtDAMPs responsible for increasing organ rejection; 2) Determine the effect of
inhibiting mtDAMPs during machine perfusion on graft preservation and post-transplant graft function; and 3)
Evaluate the ability of mtDAMP-targeting therapies to reduce human kidney injury during machine perfusion.
The results obtained by completing the aims of this proposal will be significant because they will identify
specific innate immune pathways responsible for inflammation in deceased organ donors and during ex vivo
perfusion. This knowledge will accelerate the development of candidate therapies for abrogating these
responses and mitigating graft injury prior to transplant, thus expanding organ utilization and improving organ
quality. Treating grafts pre-implantation as a strategy to reduce immune responses following transplant and
reduce rates of rejection, or to improve organ quality ex vivo, is innovative, and represents a paradigm shift for
strategies aimed at improving transplant outcomes. The knowledge gained though completion of this project
will provide a foundation to support subsequent studies, including human clinical t...

## Key facts

- **NIH application ID:** 10029329
- **Project number:** 1R01AI153274-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Andrew Serghios Barbas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $407,613
- **Award type:** 1
- **Project period:** 2020-08-17 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029329

## Citation

> US National Institutes of Health, RePORTER application 10029329, Improving transplant organ survival through the mitigation of donor-derived mitochondrial damage-associated molecular patterns (1R01AI153274-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10029329. Licensed CC0.

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