Unraveling the Molecular Mechanisms of Phagocytosis(RMI)

描述（由申请人提供）：吞噬作用是一种特殊形式的内吞作用，其中大颗粒（如微生物和死细胞）通过称为吞噬体的大内吞囊泡摄入。在哺乳动物中，三类白色血细胞充当专职吞噬细胞：巨噬细胞、嗜中性粒细胞和树突细胞。这些细胞通过摄入入侵的病原体来保护我们免受感染。巨噬细胞在清除衰老细胞和因凋亡而死亡的细胞中也具有重要作用。从数量上讲，清除死细胞是迄今为止最重要的：例如，我们的巨噬细胞每天吞噬超过1011个衰老的红细胞。虽然已知多种细胞元件参与吞噬作用，但该途径的调节仍然不清楚。例如，目前还不清楚哪些膜被募集用于形成吞噬体，以及在哪些条件下每个隔室被动员。目前还不清楚哪些蛋白质参与了这一过程（特别是融合蛋白）。在本申请中，我们寻求解决这些问题。通过使用基于荧光乳胶珠的细胞测定，我们将研究1-哪些化合物影响不同大小颗粒的内化，以及2-哪些调控元件参与其中。了解吞噬体形成和成熟的分子机制对于发现新的药物靶点和开发各种感染性疾病的新治疗方法至关重要。重新出现的主要传染病是由结核分枝杆菌（以及牛分枝杆菌）引起的结核病。M.结核病是利用宿主细胞吞噬机制进入细胞内部并逃避免疫监视的几种病原体之一。

DESCRIPTION (provided by applicant): Phagocytosis is a special form of endocytosis in which large particles such as microorganisms and dead cells are ingested via large endocytic vesicles called phagosomes. In mammals, three classes of white blood cells act as professional phagocytes: macrophages, neutrophils and dendritic cells. These cells defend us against infection by ingesting invading pathogens. Macrophages have also an important role in scavenging senescent cells and cells that have died by apoptosis. In quantitative terms, the scavenging dead cells are by far the most important: our macrophages phagocytose more than 1011 senescent red blood cells in each of us every day, for example. Although multiple cellular elements are known to be involved in phagocytosis, the regulation of this pathway is still obscure. For example, it is unclear which membranes are recruited for the formation of the phagosome and under which conditions each compartment is mobilized. It is also unclear which proteins are involved in the process (in particular the fusion proteins). In this application, we seek to address these questions. By using a cell assay based on fluorescent latex beads, we will investigate 1- which compounds are influencing the internalization of different size particles and 2- which regulatory elements are involved. Understanding the molecular mechanism of phagosome formation and maturation is fundamental for the discovery of new drug targets and the development of new treatments for a wide variety of infectious diseases. The leading re-emerging infectious disease is tuberculosis caused by mycobacterium tuberculosis (and to much lesser extent mycobacterium bovis). M. tuberculosis is one of several pathogens that exploit host cell phagocytic machinery to gain access to the cell interior and to escape immune surveillance.