This Mentored Research Scientist Development Award (K01) application describes a career development and research plan designed to position me as an independent investigator in immunological mechanisms of dendritic cell (DC) S1P1 and S1P3 dependent transplant rejection. The main research focus is progression of delayed graft function (DGF) to acute rejection in transplantation, a significant clinical problem associated with high morbidity and mortality, which predisposes individuals to chronic renal disease and loss of graft or even death. Furthermore, ischemia dependent DGF is a major determinant of organ function in transplantation, leading to long-term deleterious effects, including increased rate of acute and chronic rejection as a consequence of enhancement of inflammatory immune response. Kidney inflammation is well-established as a major pathogenic factor in acute rejection. My work as a postdoctoral fellow has recently revealed a novel role of kidney proximal tubule sphingosine-1-phosphate-receptor-1 (S1P1) activation. Kidney proximal tubule S1P1 activation protects kidneys from IRI. In addition, DCs lacking the S1P3 are unable to induce an innate immune response after kidney IRI and lack of S1P3 prolongs graft survival in skin and heart transplantation studies. Additionally, VPC01091 (S1P1 agonist and S1P3 antagonist) treatment prolongs skin graft survival and protects kidneys from IRI. We hypothesize the activation of S1P3 and inhibition of S1P1 on DC regulates DC maturation, which initiates inflammation leading to DGF and acute rejection. In the current proposal, we will elucidate: 1) the role of DC S1P1 and S1P3 activation in rodent kidney transplantation model by using genetic approaches (use of S1pr3-/- and DC specific S1pr1-/- mice), 2) the role of S1P receptor agonist, VPC01091, pharmacological approach in kidney transplantation, and 3) in-vitro mechanisms of DC maturation and activation using DCs deficient of S1P1 and S1P3. The knowledge gained from this project will reveal new aspects of DC physiology and will provide information that can be a foundation for future pre-clinical and clinical studies to explore the therapeutic potential of VPC01091 in transplantation. Through this research plan we will 1) become proficient with rodent kidney transplant model, 2) utilize in-vivo and in-vitro immunological assays to determine the mechanisms of graft survival that are pertinent to kidney disease, and 3) develop a comprehensive understanding of the physiology of DCs, in the context of kidney injury (from target cells of innate/adaptive immunity, to mechanisms of DC maturation, to trafficking patterns during injury, to the pharmacology of an S1P agonist and antagonist in DCs) with the ultimate goal of establishing and funding an independent laboratory focused on cures and treatments for chronic kidney diseases. The results of this research project will be used in the preparation of an independent NIH funded R01 application that will be submitted in the latter part of the K01 award. The career development plan includes thorough training in kidney transplantation under the guidance of Dr. Anupam Agarwal at the outstanding George F. O'Brien Center (Core B) at the University of Alabama (UAB), didactic course work to equip me with advanced and comprehensive knowledge of immunology, which will complement existing knowledge of mechanisms of kidney injury. For this award, I will be mentored by Dr. Mark Okusa, a recognized expert in immune mechanisms of kidney injury. Additional assistance in planning, troubleshooting, and interpreting results will be provided by Dr. Peter Lobo (consultant) for expertise in transplantation and Dr. Kevin Lynch for expertise in pharmacological compounds (VPC01091). After successful completion of this training program, I will emerge well-equipped to establish an independent research career in exploring the role of sphingosine receptors in transplantation with focus on adaptive immune response and role of sphingolipid receptors and kinases in chronic rejection.
As of March 2, 2011 2:40 pm Eastern Time, the Organ Procurement and Transplantation Network (http://optn.transplant.hrsa.gov/data/) shows 110,550 candidates who are on a waiting list for organ transplant, of which 87,981 are for kidney transplants. Current treatment strategies are mainly limited to supportive care and new therapeutic interventions to prevent and treat delayed graft function are urgently needed. Exploring dendritic cell-based mechanisms of protection and therapeutic potential in pre-clinical models is essential to determine whether these cells can be used to prevent and treat kidney disease in humans.
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