In vivo behavior of monocytes in resting and inflammatory conditions

 描述（由申请人提供）：巨噬细胞（Macrophages）是免疫系统最重要的防御者之一，通过保护免受感染和损伤，但它们也加速了许多疾病。近年来的研究表明，许多组织细胞在胚胎发育过程中产生，并在成年后保持稳定状态。然而，在患病组织中，许多Mc源自循环单核细胞（Mo）。例如，我们发现循环中的钼经常渗透缺血性心肌、动脉粥样硬化斑块和生长中的肿瘤，在那里它们分化成钼，并可能促进疾病。这些循环Mo可以从不同的储库位置（包括骨髓和脾脏）大量释放，并且各种疾病通过局部扩增造血干细胞和祖细胞（HSPC）来增强这些储库中的Mo产生。目前，缺乏对疾病诱导的MSPs反应的准确理解，需要在生物体水平上对这些细胞的起源和动力学进行更全面的分析。本申请中提出的研究将根据组织来源来定义组织基质的数量和质量。我们提出，在疾病中，不同的解剖部位产生不同类型的MSPs前体，因此，我们将测试的假设，即疾病相关的组织MSPs的反应可以通过操纵这些细胞的拓扑个体发生源定制。首先，通过考虑整个HSPC MMPs谱系，我们将确定定义疾病相关MMPs数量的最重要动力学过程（目的1）。第二，通过考虑这些MSPs的不同来源，我们将揭示在体内影响其质量的成熟途径（目的2）。我们的发现具有治疗潜力，因为在这两个目标中，我们将定义Ang II通路操纵如何控制MMPs。血管紧张素II是一种新鉴定的HSPC/Mo/MMP介导的炎症的艾德驱动因子，在多种疾病（癌症、动脉粥样硬化、心肌梗死）中具有活性，可被FDA批准的药物靶向。我们的目标是开发新的进展，可用于抑制不必要的炎症反应或促进保护性免疫向组织的传递。我们的实验将使用所谓的KP肿瘤小鼠模型，因为我们已经生成的数据表明：i）KP肿瘤中的MMPs具有显性表型并促进疾病; ii）这些MMPs中的许多来源于骨髓和脾脏中产生的HSPC和Mo; iii）KP小鼠中的HSPC MMPs MMPs谱系扩增类似于在其他疾病模型（包括心肌梗死和动脉粥样硬化）中观察到的扩增;和iv）激素血管紧张素（Ang）II在KP小鼠中放大疾病促进性MMPs。此外，我们还组建了一个成像、白细胞转移、数据建模和综合生物学方面的专家团队，以实现我们的目标。

 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.