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，它们各自在对肾损伤的先天反应和随后的修复过程中的作用，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体的起源和功能; 2）研究gpNMB的表达和功能，gpNMB是一种由不同的肾脏巨噬细胞亚群选择性表达的分子，可能介导修复和重塑。 候选人具有研究炎症巨噬细胞及其在肾损伤和修复中的作用的经验，并已在该领域发表文章。两年前，他从英国萨维尔教授的小组转到了哈佛邦文特教授的小组，以便更专注于组织修复的动物模型，尤其是与肾脏相关的模型。在Bonventre实验室的科学环境中补充他在巨噬细胞研究方面的背景，使候选人能够提出与肾损伤和修复期间体内巨噬细胞生物学相关的新假设。候选人现在有相当多的初步数据。他将掌握提案中的许多体内技术，包括骨髓嵌合体谱系追踪，Cre-Lox技术和肾脏损伤和修复的可重复建模。此外，拟议的研究将使获得蛋白质组学，激光捕获显微切割，逆转录病毒基因表达/沉默和分子克隆的技能。在Bonventre实验室和附近的哈佛医学院有一些有成就的同事，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，巨噬细胞会导致瘢痕形成和器官损伤。然而，相同的细胞类型是协调修复的主要免疫细胞。有人提出，这种矛盾的原因是，有两种不同类型的组织巨噬细胞。我的目标是定义这两种类型的巨噬细胞，以便开发针对一种类型的新疗法。

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.