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

在我自己之前的工作中，我可以确定常驻组织巨噬细胞（RTM）作为基质完整性的抗炎保护剂。然而，驱动和调节这种组织保护功能的潜在分子机制迄今尚未得到研究，主要是由于技术限制。然而，了解RTM是如何运作的，不是孤立的，而是在实际的基质中，这是在炎症性疾病中靶向巨噬细胞治疗不可或缺的先决条件，并且具有深远的跨学科意义，例如在癌症免疫学或疫苗学中。最近的技术进步使我能够在RTM的自然组织微环境中以高水平的细节直接全面地研究RTM。在我的拨款申请中，我提出了一种探索性的组织生物学方法，旨在从多个层面上评估RTM原位激活的分子和细胞决定因素，整合组织水平的成像数据以及转录细胞谱。具体而言，我建议广泛表征关键炎症信号通路的时空动态及其在组织环境中不同挑战下间质RTM激活的功能含义。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，不仅可以治疗炎症性疾病，而且实际上可以在组织稳态水平上预防它们。

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.