DEFINING INJURIOUS & REPARATIVE MACROPHAGES IN KIDNEY INJURY AND REPAIR

描述(由申请人提供)： 项目摘要：该项目将定义两种不同的炎性巨噬细胞谱系，确定它们的细胞起源，它们在对肾脏损伤的先天反应和随后的修复过程中的各自作用，并确定可能调节一种不同巨噬细胞谱系的吞噬功能的关键决定因素的作用。为了进行这个项目，候选人将：1)确定肾脏中不同巨噬细胞群的来源和功能；2)研究GPNMB的表达和功能，GPNMB是一种由不同亚群的肾脏巨噬细胞选择性表达的分子，可能介导修复和重塑。 这位候选人有研究炎性巨噬细胞及其在肾脏损伤和修复中的作用的经验，并在这一领域发表了论文。两年前，他从英国萨维尔教授的团队转到哈佛的邦文垂教授团队，以便更多地专注于组织修复的动物模型，尤其是与肾脏相关的动物模型。他在巨噬细胞研究方面的背景与Bonventre实验室的科学环境相辅相成，使候选人能够提出与肾脏损伤和修复过程中体内巨噬细胞生物学有关的新假说。这位候选人现在有了相当多的初步数据。他将掌握该提案中的许多体内技术，包括通过骨髓嵌合体进行血统追踪、CRE-Lox技术以及肾脏损伤和修复的可重复建模。此外，拟议的研究将使人们能够获得蛋白质组学、激光捕获显微切割、逆转录病毒基因表达/沉默和分子克隆方面的技能。在Bonventre实验室和附近的哈佛医学院都有有成就的同事，他们将在这些领域的发展中提供帮助。相关性：在目前缺乏治疗的影响肾脏的常见疾病中，巨噬细胞会导致疤痕形成和器官损伤。然而，同样的细胞类型是协调修复的主要免疫细胞。有人提出，这一悖论的原因是存在两种截然不同的组织巨噬细胞。我的目标是定义这两种类型的巨噬细胞，这样就可以开发出针对一种类型而不是另一种类型的新疗法。

DESCRIPTION (provided by applicant): Project Summary: This project will define two distinct lineages of inflammatory macrophages, determine their cellular origins, their respective roles in the innate response to kidney injury and subsequent processes of repair, and identify the role of a key determinant that may regulate the phagocytic function of one distinct macrophage lineage. In order to carry out this project the candidate will: 1) Determine the origins and functions of distinct populations of macrophages in the kidney; 2) study the expression and function of gpNMB, a molecule expressed selectively by a distinct subpopulation of kidney macrophages that may mediate repair and remodeling. The candidate has experience working on inflammatory macrophages and their role in kidney injury and repair, and has published in this area. Two years ago he moved from Prof Savill's group in the UK to Prof Bonventre's group at Harvard in order to focus more on animal models of tissue repair, with particular relevance to the kidney. Complementing his background in the study of macrophages with the scientific environment in the Bonventre lab has resulted in the candidate's ability to propose novel hypotheses relating to the biology of macrophages in vivo during kidney injury and repair. The candidate now has considerable preliminary data. He will master many of the in vivo techniques in the proposal, including, lineage tracing by bone marrow chimerism, Cre-Lox technology and reproducible modeling of injury and repair in the kidney. In addition the proposed study will enable acquisition of skills in proteomics, laser capture microdissection, retroviral gene expression/silencing and molecular cloning. There are accomplished colleagues in the Bonventre laboratory, and nearby at Harvard Medical School who will assist in these areas of development. Relevance: In common diseases affecting the kidney currently lacking therapies, macrophages contribute to scarring and organ damage. However, the same cell-type is the principal immune cell that orchestrates repair. It is proposed that the reason for this paradox is that there are two distinct types of tissue macrophage. My goal is to define these two types of macrophage so that novel therapies can be developed to target one type over another.