Primary Investigators: Dr. K Glinton, MD
Institution: Northwestern University
Funding began in 2018.
Cardiac Allograft Vasculopathy (CAV) is the most significant contributor to long-term transplant rejection, despite advances in immunotherapy. A mechanistic understanding of the cellular processes underlying CAV is, therefore, necessary for the targeted development of better therapies to promote long-term tolerance. The process of allorecognition involves transplant antigen presentation by either donor or recipient antigen-presenting cells (APCs) to resident T-cells. The TAM family of receptors tyrosine kinases (Tyro, Axl, and MerTK) have been widely studied in the promotion of engulfment of apoptotic cells and downstream transduction of intracellular signaling that influence cell proliferation and anti-inflammatory immune response. Dysfunction of TAMs is implicated in a variety of disease states including cancer, viral infection, and autoimmune diseases; however, their influence on transplant tolerance and subsequent CAV development is not well understood.
Hypothesis 1. TAMs are important regulators of graft-related immune response and repair and that Axl, in particular, promotes the progression of CAV. Preliminary data by our group support the notion of contrasting roles of Axl and MerTK in cardiac transplant survival. While MerTK ameliorates inflammatory responses and promotes tolerance, Axl contributes to vasculopathy, observed through increased intimal thickening and vascular smooth muscle cell proliferation.
Hypothesis 2. Due to their importance in antigen presentation and T-cell activation, I further hypothesize that Axl-dependent signaling in dendritic cells promotes the differentiation and proliferation of vascular smooth muscle cells and fibroblasts, which contribute to vasculopathy.
To address this, I will utilize a well-established single MHC-II mismatch vascularized heart allograft model of CAV, making use of mice with targeted depletion of Axl. Flow cytometric and histological analyses will be carried out to assess vasculopathy through immune cell infiltration, intimal thickness, and extracellular matrix staining. Furthermore, inflammatory cytokine levels will also be assessed by standard biochemical assays (ELISA, Western blotting). Long-term graft survival will be evaluated for rejection by routine palpitations. The efficacy of pharmacological inhibition of Axl will also be evaluated.
Such studies will provide invaluable insight into the general of allograft tolerance that will enable more precise therapeutic targeting in the future. I expect to gain significant knowledge about hybrid blood pump technology and its clinical relevance to treating pediatric patients, in alignment with the mission of the American Heart Association.
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