Graft-versus-host-disease (GVHD) is a life threatening complication of hematopoietic stem cell transfer (HSCT) and is the major factor in failure of HSCT. Current treatment of GVHD most commonly involves the use of immunosuppressive drugs and hence places the recipient in an immunocompromised state. Strategies that allow HSCT without the complication of GVHD would open the possibility of broader use of HSCT in the treatment of several hematologic malignancies. The major obstacle for routine use of HSCT is the profound complications that can occur from GVHD. It is well known that GVHD is mediated by activated T cells therefore an early approach was to completely delete T cells from the donor cell population prior to transfer. While this approach eliminated GVHD, it also profoundly inhibited effective engraftment as well as development of the therapeutic graft-versus-leukemia (GVL) response. Therefore current protocols include T cells in the donor cell population. This results in a high incidence of GVHD in adults receiving HSCT. Our preliminary data, presented in this application, supports a role for substrates of y-secretase in GVHD. Our data clearly demonstrate that substrates of y-secretase play an important role in GVHD and treatment of recipients with GSI inhibits GVHD. We also show that GVHD is accompanied by activation of Notch1 in donor T cells, suggesting that an important target of GSI in GVHD is Notch1. Lastly our studies with Notch deficient T cells firmly establish that Notch is one relevant target of GSI in these experiments. The experiments in this project are designed to test the hypothesis that y-secretase inhibitors may have significant clinical utility in the treatment of GVHD while maintaining graft-versus-leukemia (GVL). We then propose a series of experiments to determine the mechanisms by which y-secretase inhibitors function to block GVHD and suggest that such an understanding may lead to rational mechanistic based approach to the treatment of GVHD.
This project will allow for a better understanding of the factors that lead to a debilitating disease that frequently accompanies hematopoietic stem transfer. Experiments are proposed to both identify factors that lead to graft versus host disease, as well as, to suggest treatments that may prove efficiacious in the treatment of this disease.
|Aquila, Giorgio; Fortini, Cinzia; Pannuti, Antonio et al. (2017) Distinct gene expression profiles associated with Notch ligands Delta-like 4 and Jagged1 in plaque material from peripheral artery disease patients: a pilot study. J Transl Med 15:98|
|Sgolastra, Federica; Backlund, Coralie M; Ilker Ozay, E et al. (2017) Sequence segregation improves non-covalent protein delivery. J Control Release 254:131-136|
|Ran, Yong; Hossain, Fokhrul; Pannuti, Antonio et al. (2017) ?-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol Med 9:950-966|
|Sarapas, Joel M; Backlund, Coralie M; deRonde, Brittany M et al. (2017) ROMP- and RAFT-Based Guanidinium-Containing Polymers as Scaffolds for Protein Mimic Synthesis. Chemistry 23:6858-6863|
|Moyano, Daniel F; Liu, Yuanchang; Ayaz, Furkan et al. (2016) Immunomodulatory effects of coated gold nanoparticles in LPS-stimulated in vitro and in vivo murine model systems. Chem 1:320-327|
|Caffrey, Leah M; deRonde, Brittany M; Minter, Lisa M et al. (2016) Mapping Optimal Charge Density and Length of ROMP-Based PTDMs for siRNA Internalization. Biomacromolecules 17:3205-3212|
|Su, Ren-Wei; Strug, Michael R; Jeong, Jae-Wook et al. (2016) Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility. Proc Natl Acad Sci U S A 113:2300-5|
|Crabtree, Judy S; Singleton, Ciera S; Miele, Lucio (2016) Notch Signaling in Neuroendocrine Tumors. Front Oncol 6:94|
|Ozay, E Ilker; Gonzalez-Perez, Gabriela; Torres, Joe A et al. (2016) Intracellular Delivery of Anti-pPKC? (Thr538) via Protein Transduction Domain Mimics for Immunomodulation. Mol Ther 24:2118-2130|
|Pannella, Micaela; Caliceti, Cristiana; Fortini, Francesca et al. (2016) Serum From Advanced Heart Failure Patients Promotes Angiogenic Sprouting and Affects the Notch Pathway in Human Endothelial Cells. J Cell Physiol 231:2700-10|
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