Model system for genetic and chemical probing of tertiary lymphoid organ formation

肺部每天都暴露在灰尘和微生物中。肺的免疫系统在应对这些压力/威胁以保护宿主方面是有效的，但解释这种效率的机制仍然被误解。一种名为可诱导支气管相关淋巴组织的结构最近被证明可以增强肺部对微生物的防御，并足以清除针对呼吸道的病毒(如引起流感的病毒)。尽管可诱导的支气管相关淋巴组织的重要性与日俱增，但其形成机制仍存在误解。鞘磷脂(一类内源性信号分子)最近成为肺免疫系统的关键调节因子。尽管鞘脂可能是可诱导的支气管相关淋巴组织形成的决定因素，但它们在这一过程中的作用仍不清楚。因此，这个项目的目标是确定鞘脂如何调节可诱导的支气管相关淋巴组织的形成。我们将描述对微生物反应的可诱导的支气管相关淋巴组织形成的小鼠模型。然后，我们将制定策略，通过各种实验试剂来靶向参与这一过程的细胞。一系列的遗传策略(基因失效)和化学策略(抑制或激活特定靶点的分子)将结合在一起，描述鞘脂如何调节可诱导的支气管相关淋巴组织形成的许多步骤。确定可诱导的支气管相关淋巴组织是如何发育的，将进一步加深我们对肺免疫系统如何工作的理解。该计划还将推进在肺免疫防御背景下研究信号脂质的实验策略。该项目将培养免疫学、肺部生物学和信号血脂领域的高素质人才。我们的结果将被记录在小生物活性分子和肺部生物学领域的专门期刊上，以及关于免疫调节和细胞生物学的广泛感兴趣的期刊上。

Lungs are exposed daily to dust and microbes. The immune system of the lung is efficient at responding to these stresses/threats to protect the host, but mechanisms explaining this efficiency are still misunderstood. A structure called inducible bronchus-associated lymphoid tissue was recently shown to enhance pulmonary defense against microbes, and to be sufficient for clearance of viruses targeting the airways (like viruses causing flu). In spite of the increasing importance of inducible bronchus-associated lymphoid tissue, the mechanisms involved in its formation are misunderstood. Sphingolipids (a class of endogenous signaling molecules) lately emerged as key regulators of the pulmonary immune system. Although, sphingolipids are likely determinants of inducible bronchus-associated lymphoid tissue formation, their contribution to this process is still unknown. The goal of this program is thus to define how sphingolipids regulate inducible bronchus-associated lymphoid tissue formation. We will characterize murine models of inducible bronchus-associated lymphoid tissue formation in response to microbes. Then, we will develop strategies to target cells involved in this process with various experimental agents. An array of genetic (invalidation of genes) and chemical strategies (molecules that inhibit or activate specific targets) will be combined to delineate how sphingolipids regulate the numerous steps of inducible bronchus-associated lymphoid tissue formation. Determining how inducible bronchus-associated lymphoid tissue develops will further our understanding of how the pulmonary immune system works. This program will also advance experimental strategies to study signaling lipids in the context of pulmonary immune defense. This program will result in the training of highly qualified personnel in the fields of immunology, lung biology and signaling lipids. Our results will be documented in specialized journals in the fields of small bioactive molecules and lung biology; as well as in broad interest journals with topics of regulation of immunity and cell biology.