Mechanisms of cell corpse clearance

细胞尸体清除机制

基本信息

批准号：
8187814
负责人：
Kimberly A McCall
金额：
$ 31.07万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-05 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8187814
关键词：
Animal Model Animals Antibodies Bioinformatics Candidate Disease Gene Caspase Cell Death Cell Death Signaling Process Cell Separation Cells Complement DNA Microarray Chip Data Defect Development Drosophila genus Epithelial Epithelial Cells Excision Gene Proteins Genes Genetic Genetic Screening Goals Homeostasis Human Human body Immune System Diseases Immune response In Situ Hybridization Inflammation Label Lead MAPK14 gene MAPK8 gene Molecular Molecular Profiling Nerve Degeneration Neuroglia Nurses Ovary Pathway interactions Phagocytes Phagosomes Process Proteomics RNA Interference Reporter Research Project Grants Role Signal Transduction Signaling Molecule Starvation Surveys System Tissues Transgenic Organisms cell type egg fly gene function human disease insight macrophage molecular marker mutant network models prevent research study

Animal Model Animals Antibodies Bioinformatics Candidate Disease Gene Caspase Cell Death Cell Death Signaling Process Cell Separation Cells Complement DNA Microarray Chip Data Defect Development Drosophila genus Epithelial Epithelial Cells Excision Gene Proteins Genes Genetic Genetic Screening Goals Homeostasis Human Human body Immune System Diseases Immune response In Situ Hybridization Inflammation Label Lead MAPK14 gene MAPK8 gene Molecular Molecular Profiling Nerve Degeneration Neuroglia Nurses Ovary Pathway interactions Phagocytes Phagosomes Process Proteomics RNA Interference Reporter Research Project Grants Role Signal Transduction Signaling Molecule Starvation Surveys System Tissues Transgenic Organisms cell type egg fly gene function human disease insight macrophage molecular marker mutant network models prevent research study

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项目摘要

DESCRIPTION (provided by applicant): The efficient removal of dead cells is an important process in animal development and homeostasis. Cell corpses are often engulfed by professional phagocytes such as macrophages. However, some tissues have limited accessibility to circulating cells, and engulfment is carried out by neighboring non-professional phagocytes such as epithelial cells. The mechanisms of cell corpse recognition, engulfment and phagosome breakdown are only partially understood. The Drosophila ovary provides an excellent system for the study of engulfment by non-professional phagocytes. The ovary is closed to circulating cells, and degeneration of entire egg chambers can be induced easily by starvation. In such degenerating egg chambers, the germline nurse cells are engulfed by the surrounding somatic follicle cells. This engulfment process happens synchronously and rapidly at the onset of cell death, however the genetic requirements for follicle cell engulfment are completely unknown. This proposal aims to identify the genes and pathways required for engulfment by follicle cells. First, known engulfment genes and candidate signaling molecules will be investigated for their role in engulfment by follicle cells. Second, engulfing follicle cells will be isolated and their expression profiles will be compared to non-engulfing follicle cells using DNA microarray and proteomic approaches. Third, genetic screens will be conducted to identify new engulfment genes. Genes identified through these approaches will be characterized for their roles in engulfment in follicle cells and other tissues. These findings are expected to reveal the signaling mechanisms that are required for an epithelial cell to switch to an engulfing cell state. As the mechanisms of engulfment are highly conserved, these findings will have implications for the understanding and treatment of human diseases, including neurodegenerative and auto-immune disorders. PUBLIC HEALTH RELEVANCE: Billions of cells die every day in the human body, and these cells must be removed to prevent inappropriate immune responses. Defects in cell clearance can lead to inflammation and auto-immune disorders. This project will determine the genetic control of engulfment mechanisms in a tractable model organism.

描述（由申请人提供）：有效去除死细胞是动物发育和稳态的重要过程。细胞尸体通常被巨噬细胞等专业吞噬细胞所吞没。但是，某些组织对循环细胞的可及性有限，并且邻近的非专业吞噬细胞（例如上皮细胞）进行了吞噬。细胞尸体识别，吞噬和吞噬体崩溃的机制仅被部分理解。果蝇卵巢为非专业吞噬细胞吞噬提供了一个极好的系统。卵巢封闭于循环细胞，整个卵室的变性很容易通过饥饿诱导。在这种退化的卵室中，种系护士细胞被周围的体细胞细胞吞没。这种吞噬过程在细胞死亡开始时同步和快速地发生，但是卵泡细胞吞噬的遗传要求是完全未知的。该建议旨在确定卵泡细胞吞噬所需的基因和途径。首先，将研究已知的吞噬基因和候选信号分子，以研究其在卵泡细胞中吞噬的作用。其次，将分离吞噬卵泡细胞，并使用DNA微阵列和蛋白质组学方法将其表达谱与非刚卵泡细胞进行比较。第三，将进行遗传筛选以识别新的吞噬基因。通过这些方法鉴定的基因将以它们在卵泡细胞和其他组织中的吞噬中的作用来表征。这些发现有望揭示上皮细胞切换到吞咽细胞状态所需的信号传导机制。由于吞噬的机制是高度保守的，因此这些发现将对对人类疾病的理解和治疗（包括神经退行性和自身免疫性疾病）具有影响。公共卫生相关性：数十亿个细胞每天在人体中死亡，必须去除这些细胞以防止不适当的免疫反应。细胞清除的缺陷会导致炎症和自身免疫性疾病。该项目将确定可处理模型生物体中吞噬机制的遗传控制。