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 (M?s). Cutting edge findings reveal novel molecular links between innate M?s, and cells of the post-transplant chronic and adaptive immune response. This proposal will test the overall hypothesis that the consequences of innate M? 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 M?s. 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.

Public Health Relevance

Thorp/Luo Immune cell receptors known as TAMs promote injury repair and potentially, transplant tolerance. Inefficient perioperative repair, such as after the death of heart cells during transplant reperfusion, permits increased cell death and elevated ischemia reperfusion injury and graft- reactivity. The studies outlined herein are the first to test the clinical relevance and mechanistic basis of targeting TAMs after cardiac transplant.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL139812-01
Application #
9421990
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Schwartz, Lisa
Project Start
2018-01-15
Project End
2021-12-31
Budget Start
2018-01-15
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611