CSF1 IL34 and the function of Macrophages in Avian Development

巨噬细胞是巨大的白细胞，是抵御病原体的第一道防线，但也是感染性和炎症性疾病的主要病理因素。巨噬细胞也是体内细胞废物处理系统，它们是伤口愈合和正常发育的许多方面所必需的。鸡之所以引起人们的兴趣，是因为它们是一种重要的经济牲畜物种，它们是研究发育的易驯化模型，它们是可能影响人类的疾病的媒介，包括导致食物中毒和禽流感的细菌。该项目旨在了解鸟类中巨噬细胞的产生是如何控制的，以及巨噬细胞在胚胎发育中的功能。我们的假设是，两种生长因子，巨噬细胞集落刺激因子(CSF-1)和白介素34(IL-34)通过共同的受体(CSF-1受体)作用于促进胚胎中巨噬细胞的产生、迁移和功能。反过来，巨噬细胞是胚胎器官形成和整体生长的正常过程所必需的。为了解决这一假设，我们建议制造转基因动物，在其中所有的巨噬细胞都被标记上荧光转基因，这样我们就可以监测它们何时出现以及它们在胚胎中如何移动。我们将把这两种生长因子作为重组蛋白，并制造抗体来阻止它们的作用。最后，我们将通过将这些因子或抗体引入卵子中发育中的胚胎来检验这一假设，看看巨噬细胞的产生或位置是否可以改变，以及这是否会改变正常发育的过程。这些实验在哺乳动物身上是不容易完成的，因为胚胎不能在子宫中获得。如果我们的假设是正确的，我们将确定候选的鸡免疫和生长调节因子，并深入了解可能与理解人类怀孕和发育缺陷相关的正常发育。

Macrophages are large white blood cells that are the first line of defense against pathogens, but also contribute to much of the pathology of infectious and inflammatory disease. Macrophages are also the bodies cellular waste disposal system, and they are needed for wound healing and for many aspects of normal development. Chickens are of interest because they are an economically important livestock species, they are tractable model in which to study development, and they are vectors for diseases that can affect humans including bacteria that cause food poisoning and avian influenza. This project aims to understand how the production of macrophages is controlled in birds and the function of macrophages in embryonic development. Our hypothesis is that two growth factors, macrophage colony-stimulating factor (CSF-1) and interleukin 34 (IL-34) act through a common receptor (the CSF-1 receptor) to promote the production, migration and function of macrophages in an embryo. In turn, the macrophages are needed for the normal process of organ formation and overall growth in the embryo. To address this hypothesis, we propose to make transgenic animals in which all of the macrophages are tagged with a fluorescent transgene so we can monitor when they appear and how they move about in the embryo. We will make the two growth factors as recombinant proteins, and make antibodies that prevent their actions. And finally, we will test the hypothesis by introducing the factors, or antibodies, into the developing embryo in the egg, to see whether macrophage production or location can be altered, and whether this changes the course of normal development. These are experiments that cannot be done easily in mammals, because the embryo cannot be access in the uterus. If our hypothesis is correct, we will identify candidate modulators of chicken immunity and growth, and also gain an insight into normal development that might be relevant to understanding human pregnancy and developmental defects.