Fibroproliferation in Bronchiolitis Obliterans Syndrome

描述(由申请人提供)： 闭塞性细支气管炎综合征(BOS)是肺移植术后死亡的主要原因。免疫抑制或抗炎治疗未能有效地预防或延缓疾病的进程，已将注意力集中在纤维增殖在其发病机制中的作用。这种模式可能涉及一种有利于促纤维化的而不是抗纤维化的介质的失衡，导致成纤维细胞的募集、增殖和表型转变为更具侵略性的肌成纤维细胞，具有高合成胶原的能力。我们发现肺移植受者的支气管肺泡灌洗液(BALF)中可以培养出成纤维细胞，在BOS患者中，成纤维细胞表现为活化的表型。我们假设，促纤维化环境的形成(BALF中促纤维化介质和抗纤维化介质的比例增加)和成纤维细胞的表型改变是BOS临床发展中的关键事件。为了验证这一假设，我们将首先研究一组BOS患者的相关促纤维化和抗纤维化生物标志物的水平以及成纤维细胞的表型，并将他们与非BOS患者进行比较(病例对照研究，目标1)。其次，为了研究这种相关性随时间和事件的时间顺序，我们将连续测量这些生物标记物，并纵向研究肺移植后患者群体中成纤维细胞的表型特征(前瞻性队列研究，目标2)。 这一奖项将为首席研究员提供一个机会，使其成为一名具有肺移植翻译研究专业知识的临床研究人员。K-23将提供必要的额外经验、教学培训和指导，以培养过渡到独立资助的调查员所需的技能。培训计划的一个组成部分将包括在缺失数据管理、纵向数据分析、生存终点顺序监测和非参数生存分析方面的高级教学培训。这些数据分析模式将被用来实现具体目标，从而为候选人提供实践经验。此外，候选人将直接接受与共同导师费尔南多·J·马丁内斯医学硕士和马克·彼得斯-黄金医学博士的一对一会议的指导，这两人都是资金雄厚的研究人员，有着长期的指导记录。

DESCRIPTION (provided by applicant): Bronchiolitis Obliterans Syndrome (BOS) is the major cause of mortality after lung transplantation. Failure of immunosuppressive or anti-inflammatory therapies to meaningfully prevent or attenuate the course of the disease has focused attention on the role of fibroproliferation in its pathogenesis. Such a paradigm might involve an imbalance favoring pro-fibrotic over anti-fibrotic mediators, leading to fibroblast recruitment, proliferation and change in phenotype to more aggressive myofibroblasts with a high capacity for collagen synthesis. We have made the novel observation that fibroblasts can be cultured from the bronchoalveolar lavage fluid (BALF) of lung transplant recipients and appear to display an activated phenotype in cases with BOS. We hypothesize that the development of a pro-fibrotic milieu (increased ratio of BALF levels of pro- to anti-fibrotic mediators) and phenotypic alteration in fibroblasts are pivotal events in the clinical development of BOS. To test this hypothesis we will first study the levels of relevant pro- and anti- fibrotic biomarkers and the phenotype of fibroblasts in a cohort of patients with BOS and compare them to non-BOS patients (case control study, Aim 1). Second, in order to study such associations over time and the temporal sequence of events, we will serially measure these biomarkers and study phenotypic characteristics of fibroblasts longitudinally in a population of patients following lung transplant (prospective cohort study, Aim 2). This award will provide an opportunity for the Principal investigator to develop a career as a clinical researcher with expertise in translational studies in lung transplantation. A K-23 would provide the additional experience, didactic training and mentorship necessary to develop the skills necessary to transition to an independently funded investigator. An integral component of the training plan will include advanced didactic training in missing data management, longitudinal data analysis, sequential monitoring of survival endpoints and nonparametric survival analysis. These modalities of data analysis will be utilized to carry out the specific aims, thus providing practical experience to the candidate. Furthermore, the candidate will be directly mentored by one on one sessions with the co-mentors, Fernando J. Martinez MD, MS and Marc Peters-Golden MD, both of whom are well-funded researchers with a long track record of mentoring.