# TAM-Kinases in Transplant

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $627,837

## Abstract

Project Summary Abstract Thorp/Luo
The research described in this proposal will uncover the mechanistic basis and therapeutic
potential for new targets for cardiac transplant. Recent findings reinforce the hypothesis that
graft ischemia reperfusion injury/IRI is an independent risk factor for a more complicated clinical
course. Specifically, increased cardiac troponin levels 24 hours after cardiac transplant and
reperfusion are directly linked to chronic graft failure and vasculopathy. A critical component of
reperfusion injury is the innate immune response, which includes monocytes and macrophages
(Mɸs). Cutting edge findings reveal novel molecular links between innate Mɸs, and cells of the
post-transplant chronic and adaptive immune response. This proposal will test the overall
hypothesis that the consequences of innate Mɸ action during perioperative cardiac allograft IRI,
specifically govern subsequent alloreactivity, vasculopathy, and tolerance mechanisms by
Myeloid derived suppressor cells (MDSCs). Critical regulators of both inflammation and
tolerance are the TAM receptor tyrosine kinases/RTKs. TAMs, particularly MERTK, promote
actin-driven apoptotic cell phagocytosis, or efferocytosis, by Mɸs. Independently, the tyrosine
kinase domain of MERTK is also capable of transducing intracellular phospho-relay signals to
suppress immune cell-activation and potentially, promote immune-tolerance. Our preliminary
data suggest MERTK is antagonized by two mechanisms: MERTK destruction by ADAM
proteases, and intracellular signaling by another TAM family member, i.e., AXL. We hypothesize
that MERTK-mediated efferocytosis mitigates perioperative graft IRI, the consequences of
which are linked to subsequent promotion of allograft tolerance. We hypothesize suboptimal
perioperative allograft preservation, ADAM proteases, and AXL antagonize beneficial MERTK
actions. In addition to testing these hypotheses, we will also test their therapeutic potential and
human relevance.

## Key facts

- **NIH application ID:** 9840935
- **Project number:** 5R01HL139812-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Xunrong Luo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $627,837
- **Award type:** 5
- **Project period:** 2018-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840935

## Citation

> US National Institutes of Health, RePORTER application 9840935, TAM-Kinases in Transplant (5R01HL139812-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840935. Licensed CC0.

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