Apoptotic Cell-Induced Macrophage Signaling Pathways that Regulate Phagocytosis

凋亡细胞诱导的巨噬细胞信号通路调节吞噬作用

• 批准号: 8416317
• 负责人: Nathalie Claudine Franc
• 金额: $ 44.53万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416317
• 关键词: Alleles; Apoptosis; Apoptotic; Autoimmune Diseases; Autoimmunity; Biochemistry; Biological Models; CD36 gene; Calcium; Candidate Disease Gene; Cell Adhesion Molecules; Cell Line; Cell surface; Cells; Chimeric Proteins; Co-Immunoprecipitations; Communicable Diseases; Data; Defect; Development; Disease; Dissection; Drosophila genus; Eating; Excision; F Box Domain; F-Box Proteins; Failure; Genes; Genetic; Genetic Techniques; Glycoproteins; Goals; Hemocytes; Homeostasis; Host Defense; Immune response; In Situ Hybridization; Knowledge; Lead; Length; Ligands; Light; Lipoproteins; Macular degeneration; Mass Spectrum Analysis; Modeling; Molecular; Molecular Genetics; Mutate; Natural Immunity; Nature; Nerve Degeneration; Neurodegenerative Disorders; Nuclear; Nuclear Export; Organism; Pathway interactions; Phagocytes; Phagocytosis; Phospholipids; Process; Proteins; RNA Interference; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Systemic Lupus Erythematosus; Testing; base; design; fighting; genome-wide; in vivo; macrophage; migration; mutant; novel; pathogen; prevent; receptor; research study; response; scavenger receptor; therapy design; therapy development; trafficking; transcription factor; tumor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Phagocytosis is critical for the removal of pathogens in host defense, and cells that are dying by apoptosis. Failure to clear pathogens results in infectious diseases. Failure to clear apoptotic cells (ACs) can result in developmental defects, autoimmunity or neurodegeneration. There are substantial gaps in our knowledge of the molecular mechanisms of phagocytosis. We do not know how phagocytes perceive and integrate AC-signals that promote phagocytosis. Until we fill this knowledge gap, developing new strategies to prevent or treat diseases that arise from defective phagocytosis will be difficult. Our long-term goal is to genetically dissect the molecular mechanisms of AC clearance. We use Drosophila as a model system, which has allowed us to advance our understanding of AC clearance by demonstrating novel roles for receptors on phagocytes, proteasomal degradation and calcium homeostasis in this process. Our rationale is that Drosophila can serve as a model to identify evolutionary conserved regulators of phagocytosis and shed new light on its molecular mechanisms, and tell us how AC-signals activate phagocytes. Our objectives are to identify novel positive and negative regulators of phagocytosis of ACs. Our central hypotheses are that: (1) apoptosis regulates the expression of Croquemort (CRQ), a CD36-related phagocytic scavenger receptor; (2) the substrates of Pallbearer, (PALL), an F-Box protein that promotes phagocytosis via its E3-Ubiquitin ligase activity, are negative regulators of phagocytosis; and (3) apoptosis regulates the subcellular localization of PALL, which acts upstream of CRQ. These are based on data showing that CRQ expression and PALL nuclear trafficking are apoptosis-dependent, that proteasomal degradation of PALL substrates promotes phagocytosis, and that CRQ is weakly expressed in pall mutants. Our specific aims are designed to (1) identify and study the role of CRQ regulators, (2) identify the PALL substrate(s) and study its (their) role in phagocytosis, and (3) study the trafficking of PALL in response to apoptosis and its relevance to AC clearance, using genetic and RNAi screens, biochemistry and molecular genetic techniques. This proposal wil advance our understanding of the molecular mechanisms of AC clearance, and identify regulators of this process that may serve as candidate targets for the development of new therapies designed to prevent or treat autoimmune, neurodegenerative and infectious diseases.

描述（由申请人提供）：吞噬作用对于去除宿主防御中的病原体以及因凋亡而死的细胞至关重要。未能清除病原体会导致传染病。无法清除凋亡细胞（AC）会导致发育缺陷，自身免疫性或神经变性。我们对吞噬作用的分子机制有很大的差距。我们不知道吞噬细胞如何感知和整合促进吞噬作用的交流信号。在填补这一知识差距之前，很难制定新的策略来预防或治疗因缺陷吞噬作用而引起的疾病。我们的长期目标是遗传剖析AC清除的分子机制。我们使用果蝇作为模型系统，这使我们能够通过在此过程中证明受体在吞噬细胞，蛋白酶体降解和钙稳态上的新作用来提高对AC清除的理解。我们的理由是，果蝇可以用作识别吞噬作用的进化保守调节剂的模型，并为其分子机制提供新的启示，并告诉我们Ac-Signals如何激活吞噬细胞。我们的目标是确定ACS吞噬作用的新型阳性和阴性调节剂。我们的中心假设是：（1）凋亡调节Croquemort（CRQ）的表达（CRQ），这是一种与CD36相关的吞噬清除剂受体； （2）Pallbearer（PALL）的底物是一种F-box蛋白，通过其E3-泛素连接酶活性促进吞噬作用，是负调节剂 吞噬作用； （3）细胞凋亡调节PALL的亚细胞定位，该pall起作用的pall。这些基于数据表明，CRQ表达和PALL核运输是凋亡依赖性的，PALL底物的蛋白酶体降解会促进吞噬作用，并且CRQ在Pall突变体中弱表达。我们的具体目的旨在（1）识别和研究CRQ调节剂的作用，（2）确定PALL底物（S）并研究其在吞噬作用中的作用，（3）研究PALL对凋亡及其与AC清除相关的pall贩运，使用遗传和RNAI筛查，遗传和RNAI筛查，BioChemector，BioChemector，bioecter，BioChemector，bioector centic sectiquique。该提议将提高我们对AC清除的分子机制的理解，并确定该过程的调节因子，这些调节因素可能是开发旨在预防或治疗自身免疫性，神经退行性和感染性疾病的新疗法的候选靶标。