Molecular Assessment of the Acute Damage-Response in Stromal Resident Tissue Macrophages.

在我之前的工作中，我可以确定常驻组织巨噬细胞(RTM)是基质完整性的抗炎保护者。然而，驱动和调节这种组织保护功能的潜在分子机制到目前为止还没有被研究过，主要是由于技术上的限制。然而，了解RTM如何在实际基质中而不是孤立地发挥作用，是在炎症性疾病中靶向巨噬细胞的不可或缺的先决条件，具有深远的、跨学科的影响，例如在癌症免疫学或疫苗学中。最近的技术进步使我能够直接、全面地研究RTM在其自然组织微环境中的高水平细节。在我的拨款提案中，我提出了一种探索性的组织生物学方法，旨在通过整合组织水平的成像数据和转录细胞图谱，在多个水平上评估原位RTM激活的分子和细胞决定因素。具体地说，我提出了关键炎症信号通路的时空动力学的广泛表征，以及它们在间质RTM激活中的功能含义，以应对各自组织环境中的不同挑战。此外，我试图评估RTM和其他基质细胞的早期转录损伤反应，以确定新的靶点，不仅治疗炎症性疾病，而且实际上在组织内稳态的水平上预防它们。

In my own previous work, I could identify resident tissue macrophages (RTM) as anti-inflammatory protectors of stromal integrity. The underlying molecular mechanisms that drive and regulate this tissue-protective function, however, have not been studied so far, mostly due to technical limitations. Understanding how RTM operate, though, not in isolation but within the actual stroma constitutes an indispensable prerequisite for targeting macrophages therapeutically in inflammatory diseases and has far-reaching, cross-disciplinary implications, for instance in cancer immunology or vaccinology. Recent technological advances allowed me to directly and comprehensively study RTM within their natural tissue microenvironment with high level of detail. In my grant proposal, I propose an exploratory tissue biology approach, aiming to assess molecular and cellular determinants of RTM activation in situ on multiple levels, integrating tissue-level imaging data as well as transcriptional cell profiling. Specifically, I propose the extensive characterization of the spatiotemporal dynamics of key inflammatory signaling pathways and their functional implications in interstitial RTM activation upon different challenges within their own tissue environment. Further, I seek to assess early transcriptional damage responses in RTM and other stromal cells in order to identify novel targets, not only to treat inflammatory diseases but actually prevent them on the level of tissue homeostasis.