In vivo behavior of monocytes in resting and inflammatory conditions

 描述(由申请人提供)：巨噬细胞(M？)是免疫系统最重要的身体防御者之一，可防止感染和损伤，但它们也会加速许多疾病。最近的研究表明，许多组织是在胚胎发育过程中产生的，并在成年后保持稳定状态。然而，在病变组织中，许多Mä起源于循环单核细胞(Mo)。例如，我们发现fi中经常循环的钼可抑制缺血心肌、动脉粥样硬化斑块和生长中的肿瘤，在这些地方它们分化为M？并可促进疾病。这些循环中的钼可以从不同的储存库中大量释放，包括骨髓和脾，各种疾病通过局部扩增造血干细胞和祖细胞(HSPC)来促进这些储存库中钼的产生。目前，对疾病诱导的M？反应缺乏准确的了解，需要在生物体水平上更全面地分析这些细胞的起源和动力学。本申请中提出的研究将根据组织的来源来确定组织M？的数量和质量。我们认为，在疾病中，不同的解剖位置会产生不同类型的M？前体，因此我们将检验这样一种假设，即疾病相关组织的M？反应可以通过操纵这些细胞的局部个体来源来定制。首先，通过考虑整个HSPC➝Mo➝M？谱系，我们将确定导致fiNe疾病相关M？的数量(目标1)的最重要的动力学过程。其次，通过考虑这些M？的不同来源，我们将揭示在fl中它们在体内的质量的成熟途径(目标2)。我们的fi结合具有治疗潜力，因为在这两个目标中，我们都将研究fiII途径操作如何控制M？Ang II是新近发现的Hspc/Mo/M？介导的fl转导的驱动因子，在多种疾病(癌症、动脉粥样硬化、心肌梗死)中发挥作用，并可作为FDA批准的药物的靶点。我们的目标是开发新的进展，可以用来抑制不需要的fl炎性反应，或者相反，促进保护性免疫传递到组织。我们的实验将使用所谓的KP肿瘤小鼠模型，因为我们已经产生的数据表明：i)KP肿瘤中的M？具有主要的表型并促进疾病；ii)这些M？中的许多起源于HSPC和骨髓和脾中产生的Mo；iii)在KP小鼠中的HSPC➝Mo➝M？谱系扩增fi阳离子与在包括心肌梗死和动脉粥样硬化在内的其他疾病模型中观察到的相似；以及iv)激素血管紧张素(Ang)II扩增fiEs疾病促进KP小鼠中的M？此外，我们还组建了一支由成像、白细胞TRAFfi检测、数据建模和综合生物学方面的专家组成的团队来实现我们的目标。

 DESCRIPTION (provided by applicant): Macrophages (MØ) are among the immune system's most important defenders of the body by protecting against infection and injury but they also accelerate numerous diseases. Recent studies indicate that many tissue MØ are generated during embryonic development and maintain themselves in adults in the steady-state. In diseased tissues, however, many MØ originate from circulating monocytes (Mo). For example, we found that circulating Mo often infiltrate the ischemic myocardium, atherosclerotic plaques and growing tumors, where they differentiate into MØ and can promote disease. These circulating Mo can be released in large quantities from different reservoir locations, including th bone marrow and spleen, and various diseases enhance Mo production in these reservoirs by amplifying hematopoietic stem and progenitor cells (HSPC) locally. At present, an accurate understanding of disease-induced MØ responses is lacking and requires a more comprehensive analysis of the origins and dynamics of these cells at the organismal level. The research proposed in this application will define both the quantity and quality of tissue MØ based on thei origins. We propose that, in disease, distinct anatomical sites produce different types of MØ precursors and we will thus test the hypothesis that disease-associated tissue MØ responses can be tailored by manipulating these cells' topo-ontogenic sources. First, by taking the entire HSPC➝Mo➝MØ lineage into account we will identify the most important kinetic processes that define the quantity of disease-associated MØ (aim 1). Second, by considering the different origins of these MØ we will uncover maturational pathways that influence their quality in vivo (aim 2). Our findings have therapeutic potential because in both aims we will define how Ang II pathway manipulations control MØ. Ang II is a newly identified driver of HSPC/Mo/MØ-mediated inflammation that is active in a variety of diseases (cancer, atherosclerosis, myocardial infarction) and can be targeted with FDA-approved drugs. Our goal is to develop new advances that can be used to restrain unwanted inflammatory reactions or instead promote delivery of protective immunity to tissue. Our experiments will use the so-called KP tumor mouse model because we have generated data indicating that: i) MØ in KP tumors have a dominant phenotype and promote disease; ii) many of these MØ originate from HSPC and Mo that are produced in bone marrow and spleen; iii) HSPC➝Mo➝MØ lineage amplification in KP mice resembles the one observed in other disease models including myocardial infarction and atherosclerosis; and iv) the hormone Angiotensin (Ang) II amplifies disease-promoting MØ in KP mice. Also, we have assembled a team of experts in imaging, leukocyte trafficking, data modeling and integrative biology to accomplish our goals.