Role of Bai1 and Elmo Proteins in Apoptotic Cell Clearance

Bai1 和 Elmo 蛋白在凋亡细胞清除中的作用

基本信息

批准号：
8599030
负责人：
Ulrike Lorenz
金额：
$ 31.96万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8599030
关键词：
Address Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Atherosclerosis Autoimmune Diseases Autoimmunity Award BAI1 gene Binding Biology Brain Caenorhabditis elegans Cell Death Cells Cellular biology Chronic Complex DNA Sequence Rearrangement Defect Dendritic Cells Development Disease Eating Excision Failure Figs - dietary Funding Genetic Genetic Transcription Germ Cells Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Homeostasis Homologous Gene Human Inflammation Inflammatory Inflammatory Response Interleukin-10 Knock-out Knockout Mice Knowledge Laboratories Lead Link Mammalian Cell Mediating Mediator of activation protein Membrane Proteins Mus National Institute of General Medical Sciences Nature Necrosis Pathway interactions Phagocytes Phagocytosis Phosphatidylserines Physiology Play Process Production Proteins Role Secondary to Signal Pathway Signal Transduction Systemic Lupus Erythematosus Testing Testis Therapeutic Intervention Thymus Gland Tissues Transgenic Mice Transgenic Organisms Translating Up-Regulation Work adapter protein airway inflammation base cell type chemotherapy cytokine genome wide association study human disease in vivo insight macrophage member mouse model mutant neurogenesis novel overexpression receptor tumor

项目摘要

DESCRIPTION (provided by applicant): We turnover billions of cells in the body each day as part of normal homeostasis, and many of these cells die by the process of apoptosis. The apoptotic cells are quickly cleared by phagocytes in vivo, in an 'immunologically silent' fashion. Defects in prompt removal leads to secondary necrosis, with the release of intracellular contents from the dying cells promoting chronic tissue inflammation, which has been linked to autoimmune disorders such as SLE, airway inflammation, and atherosclerosis. Thus, a better knowledge of the mechanisms of apoptotic cell recognition and clearance becomes necessary for countering these disorders. This current competitive renewal application is based on the progress made during the two previous funding periods of 4 years each. We first identified a novel cytoplasmic engulfment adapter protein ELMO1, and defined the ELMO/Dock180/Rac signaling pathway as an evolutionarily conserved module for promoting apoptotic cell engulfment. We then identified the membrane protein BAI1 as the engulfment receptor upstream of ELMO1; independently, we generated knockout mice for Elmo1 to identify its requirement in apoptotic germ cell clearance in the testes, and during neurogenesis in the brain. These works have also raised a number of exciting next set of questions on signaling via the BAI1/ELMO1 module in vivo, and how this pathway may dampen inflammation in tissues. In Aim1 of this proposal, using mice recently generated in our laboratory where the Bai1 locus has been targeted for deletion (floxed as well as straight knockout), we will test the hypothesis that BAI1 plays a role in apoptotic cell clearance in vivo in two different tissues, the thymus and the testes. Moreover, using inducible transgenic mice that overexpress wild type or a mutant form of BAI1, we will test whether BAI1 provides unique versus redundant signals in promoting engulfment in vivo. Aim 2 focuses on how apoptotic cell recognition translates to anti-inflammatory cytokine production, key feature of apoptotic cell clearance that is not fully understood. We will test the hypothesis that the BAI1-ELMO1-mediated signaling contributes to anti-inflammatory responses of phagocytes. Specifically, we will test how an unexpected interaction between ELMO1 and components of the transcriptional machinery (which we have discovered in our preliminary studies), contribute to the anti-inflammatory gene transcription during engulfment. We will extend these in vivo using mice deficient in Elmo2 (that we have recently generated) in a mouse model of tissue inflammation. Collectively, we expect these studies to provide exciting new information on signaling via the BAI1/Elmo1 signaling pathway in cell clearance in vivo. Since altered expression of ELMO1 and BAI1 are genetically linked to inflammatory disorders in humans, the results from the proposed studies could be relevant for therapeutic intervention in inflammatory disorders.

描述（由申请人提供）：我们每天作为正常体内平衡的一部分，我们周转数十亿个细胞，其中许多细胞死于凋亡过程。凋亡细胞在体内迅速被吞噬细胞清除，以“免疫学上”的方式。迅速去除的缺陷导致继发性坏死，伴有垂直细胞的细胞内含量促进慢性组织炎症，这与自身免疫性疾病有关，例如SLE，气道炎症和动脉粥样硬化。因此，对凋亡细胞识别和清除的机制有了更好的了解，这对于抵消这些疾病是必要的。当前的竞争续约申请基于前两个融资期间4年的进度。我们首先确定了一种新型的细胞质吞噬适配器蛋白ELMO1，并将ELMO/DOCK180/RAC信号通路定义为用于促进凋亡细胞吞噬的进化保守模块。然后，我们将膜蛋白BAI1鉴定为Elmo1上游的吞噬受体。独立地，我们生成了ELMO1的基因敲除小鼠，以鉴定其在睾丸中凋亡生殖细胞清除率以及大脑神经发生期间的需求。这些作品还提出了许多令人兴奋的下一组问题，该问题通过体内通过BAI1/ELMO1模块发出信号，以及该途径如何抑制组织中的炎症。在该提案的AIM1中，使用最近在我们的实验室中生成的小鼠，该实验室已将BAI1基因座的靶向靶向（Floxed和Straight敲除），我们将测试BAI1在两种不同的组织，胸腺和验证者的体内中bai1在体内的凋亡细胞清除中起作用的假设。此外，使用过表达野生型或突变体Bai1的诱导转基因小鼠，我们将测试BAI1是否在促进体内吞噬吞噬的情况下是否提供了独特的信号。 AIM 2的重点是凋亡细胞识别如何转化为抗炎细胞因子的产生，这是凋亡细胞清除率的关键特征，这些特征尚未完全了解。我们将检验以下假设：BAI1-ELMO1介导的信号传导有助于吞噬细胞的抗炎反应。具体而言，我们将测试ELMO1与转录机械组件之间的意外相互作用（我们在初步研究中发现的）如何有助于吞噬期间的抗炎基因转录。我们将使用在组织炎症的小鼠模型中使用缺乏ELMO2（最近产生的）小鼠扩展这些体内体内。总体而言，我们预计这些研究将通过体内细胞清除率的BAI1/ELMO1信号通路提供有关信号传导的令人兴奋的新信息。由于ELMO1和BAI1的表达改变与人类的炎症性疾病有关，因此拟议的研究的结果可能与炎症性疾病的治疗干预有关。