Longitudinal Cohort/Sheppard

项目总结(见说明)： 由于缺乏与机制相关的终点，IPF中的临床药物开发受到阻碍。纵向队列核心的主要目标是向项目1-3提供纵向临床数据和生物样本(血液和BAL)，用于识别ER应激、TGFb激活和EMT的候选分子标记。机理信息丰富的分子标记将是 在项目1-3中确定的潜在药物制剂的早期阶段研究中作为终点，在选择对象时非常有用，从而能够更快、更有效地评估生物效应。使用来自这个核心的血液和BAL，我们将展示在临床可访问的IPF患者的隔室中可以测量到候选的机械信息分子标记物。分子标志物水平将在IPF和对照受试者之间进行比较，并与基线人口统计学和临床数据相关联。 还将评估候选的机械信息分子标记的纵向稳定性。预计由纵向队列核心支持的实验将导致识别新的、机制信息丰富的ER应激、avp6介导的TGFb激活和EMT的分子标记，这些标记在IPF患者中很容易测量，并且随着时间的推移相对稳定。这些分子标记将有助于为未来药物的早期临床试验确定合适的受试者，并可能 在这些试验中充当机械敏感的终点，将在此翻译计划项目拨款的第二个5年内进行。

PROJECT SUMMARY (See instructions): Clinical drug development in IPF is hindered by the lack of mechanistically-relevant endpoints. The primary objective of the Longitudinal Cohort Core is to supply longitudinal clinical data and biological samples (blood and BAL) to Projects 1-3 to be used in the identification of candidate mechanistically-informative molecular markers of ER stress, TGFB activation, and EMT. Mechanistically-informative molecular markers would be extremely useful in subject selection and as endpoints in early phase studies of potential drug agents identified in Projects 1-3, allowing for more rapid and efficient assessment of biological effect. Using the blood and BAL from this core, we will show that candidate mechanistically-informative molecular markers are measurable in clinically-accessible compartments of patients with IPF. Molecular marker levels will be compared between IPF and control subjects, and correlated with baseline demographic and clinical data. The longitudinal stability of candidate mechanistically-informative molecular markers will also be assessed. It is anticipated that experiments supported by the Longitudinal Cohort Core will result in the identification of novel, mechanistically-informative molecular markers of ER stress, avp6-mediated TGFB activation, and EMT that are easily measurable in patients with IPF and are relatively stable over time.Such molecular markers will help identify appropriate subjects for future early-phase clinical trials of drug agents and could serve as mechanistically-sensitive endpoints in these trials, to be conducted during the second 5 years of this translational program project grant.