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

• 批准号: 8707468
• 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
• 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/8707468
• 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

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）：作为正常体内平衡的一部分，我们每天在体内循环数十亿个细胞，其中许多细胞通过凋亡过程死亡。凋亡细胞在体内以一种“免疫沉默”的方式被吞噬细胞迅速清除。及时清除的缺陷导致继发性坏死，死亡细胞释放细胞内内容物促进慢性组织炎症，这与自身免疫性疾病如SLE、气道炎症和动脉粥样硬化有关。因此，更好地了解凋亡细胞识别和清除的机制对于对抗这些疾病是必要的。目前的竞争性续期申请是基于前两个四年资助期的进展。我们首先发现了一种新的细胞质吞噬适配器蛋白ELMO1，并将ELMO/Dock180/Rac信号通路定义为促进凋亡细胞吞噬的进化保守模块。然后我们确定了膜蛋白BAI1是ELMO1上游的吞噬受体；另外，我们建立了Elmo1基因敲除小鼠，以确定其在睾丸凋亡生殖细胞清除和大脑神经发生过程中的需求。这些工作也提出了一些令人兴奋的关于体内通过BAI1/ELMO1模块信号传导的下一组问题，以及该途径如何抑制组织中的炎症。在本提案的目的1中，我们将使用我们实验室最近产生的Bai1位点被靶向删除（剔除和直接敲除）的小鼠，在胸腺和睾丸两种不同的组织中，我们将测试Bai1在体内凋亡细胞清除中起作用的假设。此外，利用诱导型转基因小鼠过度表达野生型或突变型BAI1，我们将测试BAI1在体内是否提供独特的或冗余的信号来促进吞噬。目的2侧重于凋亡细胞识别如何转化为抗炎细胞因子的产生，这是凋亡细胞清除的关键特征，目前尚不完全清楚。我们将验证bai1 - elmo1介导的信号传导有助于吞噬细胞抗炎反应的假设。具体来说，我们将测试ELMO1和转录机制组件之间的意外相互作用（我们在初步研究中发现）如何在吞噬过程中促进抗炎基因的转录。我们将在体内使用缺乏Elmo2的小鼠（我们最近生成的）在小鼠组织炎症模型中扩展这些。总的来说，我们希望这些研究能够为体内细胞清除中通过BAI1/Elmo1信号通路的信号传递提供令人兴奋的新信息。由于ELMO1和BAI1表达的改变与人类炎症性疾病有遗传联系，因此拟议研究的结果可能与炎症性疾病的治疗干预有关。