This project is based on the observation that Vascular Endothelial Growth Factor (VEGF) is overexpressed within allografts in association with ischemia-reperfusion, humoral immunity and acute and chronic rejection. Current paradigms suggest that it functions as a dominant factor mediating vascular remodeling, especially in association with chronic inflammation. However, VEGF also has potent proinflammatory effects in association with cell-mediated immune inflammation. The novelty of this research proposal relates to recent observations that the VEGF receptors (VEGFR) KDR (VEGFR2), Flt-1 (VEGFR1) and neuropilin family molecules are expressed on populations of effector, memory and FOXP3high T regulatory cells. Further, our ongoing observations indicate that VEGF-KDR interactions are potent to mediate motility and activation responses within T effector cells. In ths R01, we plan to question the interplay between VEGF and Class 3 semaphorins, classical mediators of chemorepulsion, cytoskeletal and regulatory signaling responses. We will evaluate how these molecules interact with their common neuropilin receptors expressed on T effector and T regulatory cells in the alloimmune response. Since VEGF is thought to compete with class 3 semaphorins for binding to the neuropilins, these observations beg the question whether VEGF binding may alter Sema3-inducible inhibitory/regulatory immune responses. Our hypothesis is that intragraft VEGF interacts with circulating VEGFR-expressing T cells, and that individual VEGFRs on T cell subsets elicit signals that either promote or suppress migratory and activation responses. We will test this hypothesis in three specific aims in which we will 1), determine the expression and function of VEGFRs in T cell subsets, and evaluate the interplay between VEGF and class 3 semaphorins for T cell chemotaxis, activation and immunoregulatory responses, 2), determine the effect of VEGF-neuropilin-semaphorin interactions in vivo in physiological models of allograft rejection, and 3) define NRP-2 regulated intracellular signaling pathways that function to suppress T cell activation. Our proposed studies address novel and clinically relevant questions and our approach provides for cohesiveness to translate in vitro findings into clinically relevant models in vivo. Our approach is designed so tht functional studies outlined in Aims 1 and 2 can be understood in terms of an in-depth analysis of regulatory signaling mechanisms in Aim 3. Collectively, the implications and clinical relevance of this area of investigation is that local intragraft VEGF, which is traditionally thought to serve simply as an angiogenesis factor, may be a novel factor that coordinates interactions among circulating VEGFR-expressing T effector and T regulatory cells within the graft. The overall impact of these studies is their potential to identify new immunoregulatory receptors and ligands that function to either promote or inhibit T cell activation and allograft rejection.
Organ transplantation is a lifesaving therapy for individuals with end stage organ failure, but all transplants eventually fail due to a process called chronic allograft rejection. In this research proposal, we plan to perform mechanistic studies addressing questions about the molecular basis for VEGF receptor interactions in T cells. We will also study a novel neuropilin family of receptors expressed on T cells that also bind semaphorins. These studies will provide mechanistic insight into the pathological basis for chronic rejection, and wil identify new targets with therapeutic implications.
| Wedel, Johannes; Nakayama, Hironao; Kochupurakkal, Nora M et al. (2017) The intragraft microenvironment as a central determinant of chronic rejection or local immunoregulation/tolerance. Curr Opin Organ Transplant 22:55-63 |
| Boneschansker, Leo; Nakayama, Hironao; Eisenga, Michele et al. (2016) Netrin-1 Augments Chemokinesis in CD4+ T Cells In Vitro and Elicits a Proinflammatory Response In Vivo. J Immunol 197:1389-98 |
| Bruneau, Sarah; Wedel, Johannes; Fakhouri, Fadi et al. (2016) Translational implications of endothelial cell dysfunction in association with chronic allograft rejection. Pediatr Nephrol 31:41-51 |
| Jain, Namrata G; Wong, Elisabeth A; Aranyosi, Alexander J et al. (2015) Microfluidic mazes to characterize T-cell exploration patterns following activation in vitro. Integr Biol (Camb) 7:1423-31 |
| Nakayama, Hironao; Bruneau, Sarah; Kochupurakkal, Nora et al. (2015) Regulation of mTOR Signaling by Semaphorin 3F-Neuropilin 2 Interactions In Vitro and In Vivo. Sci Rep 5:11789 |
| Wedel, Johannes; Bruneau, Sarah; Kochupurakkal, Nora et al. (2015) Chronic allograft rejection: a fresh look. Curr Opin Organ Transplant 20:13-20 |
| Boneschansker, Leo; Yan, Jun; Wong, Elisabeth et al. (2014) Microfluidic platform for the quantitative analysis of leukocyte migration signatures. Nat Commun 5:4787 |
| Bruneau, Sarah; Nakayama, Hironao; Woda, Craig B et al. (2013) DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses. Blood 122:1833-42 |
| Singh, Anup Kumar; Arya, Rakesh Kumar; Trivedi, Arun Kumar et al. (2013) Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12. Cytokine Growth Factor Rev 24:41-9 |
| Zangi, Lior; Lui, Kathy O; von Gise, Alexander et al. (2013) Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol 31:898-907 |
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