This is a Career Development Grant to allow the PI protected time for formal education, mentored laboratory work and development of a research approach. My new research pathway requires additional mentored and didactic learning, despite my extensive prior training and experience. In my over three years at UCLA I have learned new laboratory techniques that are common in the field of transplant immunology. I have become competent at FACS and analysis of such data. The complex, longitudinal studies that I propose to undertake will require statistical analysis techniques with which I am not yet familiar. Moreover, more time is needed to develop a solid laboratory background, and such experience is best gained in a mentored environment. A mentored research environment thus allows protected time for me to undertake formal instruction, to continue to apply for grant funding, and to establish myself as a translational transplant researcher. The K23 is designed to meet these goals. My Career Development Plan includes formal, graduate level, biostatistical coursework as a part of the UCLA K30 program, which will lead to a Masters in Clinical Research. More advanced courses will be taken within the Department of Biostatistics that focus on analysis of complex, longitudinal data with many covariates, which is the sort of data to be developed in the research plan. Courses outside of UCLA will focus on furthering my FACS skills and analysis of such data. The Environment and Mentors that we have put together is truly phenomenal. The resources available to me at UCLA will ensure that the aims in this grant, which includes my growth as an independent researcher, are met. My mentors have a combined history of mentoring scores of successful researchers and have solid grant support for the duration of my proposal. This is truly a multi-disciplinary approach to research and training, which is precisely the approach that science itself is more often taking. The research plan is focused on lymphocytes, chemokines, cytokines and long-term graft survival. Lung transplantation is a therapeutic option for end-stage lung disorders. Long-term survival is largely dependent upon recipients remaining free of bronchiolitis obliterans syndrome (BOS). BOS affects over 60% of lung transplant recipients within five years after transplantation and imparts a 3-year mortality of >50%. Despite BOS being a major obstacle to long-term survival post-lung transplantation, there is presently no effective means of early detection nor effective treatment strategy. We have recently found that lung transplant recipients with increased frequencies of Treg within the bronchoalveolar lavage fluid do not develop BOS. The frequencies of BAL Treg correlated with BAL levels of the CCR7 ligand CCL21, which itself appears to protect against BOS. We further identified a subset of Treg, CCR7+/CD45RA- memory Treg, that identify individuals protected from chronic allograft rejection. Our hypothesis is that these CCR7+/CD45RA- memory Treg promote an allograft milieu which protects lung allograft recipients against BOS. The overall objective of this application is to determine if a) BALF CCR7+ /CD45RA- mTreg can identify lung transplant recipients at reduced risk of future BOS development and b) if BALF protein levels of the CCR7 ligands correlate with protection from BOS and with frequencies of this Treg subset. Our long-term objective is to determine the immune mechanisms that drive BOS, so as to prolong survival and improve quality of life after lung transplantation. The successful completion of these aims will improve understanding of the mechanisms behind Treg accumulation within the lung allograft and will ultimately lead to the development of novel biologics to promote protection against BOS.
Lung transplantation is an option for end-stage lung disease, but is complicated by chronic allograft rejection (BOS). Despite its major obstacle to long-term survival, there is presently no effective means of early detection, prevention, or treatment strategies. Identification of a Treg subset responsible for preventing BOS and elucidation of the mechanism whereby such Treg are recruited to and maintained within the allograft will allow for novel therapeutic and treatment modalities to prolong post-lung transplant survival.
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