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: 8896807
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896807
• 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; Defect; Dendritic Cells; Development; Disease; Eating; Excision; Failure; Figs - dietary; Funding; Genetic Transcription; Genetic study; 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，我们每天在体内更新数十亿个细胞，其中许多细胞因细胞凋亡过程而死亡。凋亡细胞在体内被吞噬细胞以“免疫沉默”的方式快速清除。及时清除的缺陷会导致继发性坏死，垂死细胞释放细胞内内容物，促进慢性组织炎症，这与系统性红斑狼疮、气道炎症和动脉粥样硬化等自身免疫性疾病有关。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变得必要。目前的竞争性更新申请是基于前两个资助期（各 4 年）期间取得的进展。我们首先鉴定了一种新型细胞质吞噬衔接蛋白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。然后我们确定膜蛋白 BAI1 是 ELMO1 上游的吞噬受体；我们独立地培育了 Elmo1 基因敲除小鼠，以确定其在睾丸中凋亡生殖细胞清除以及大脑神经发生过程中的需求。这些工作还提出了一系列令人兴奋的下一组问题，涉及体内 BAI1/ELMO1 模块的信号传导，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生成的小鼠，其中 Bai1 基因座已被靶向删除（floxed 以及直接敲除），我们将测试 BAI1 在两种不同组织（胸腺和睾丸）体内凋亡细胞清除中发挥作用的假设。此外，使用过度表达野生型或突变型 BAI1 的诱导型转基因小鼠，我们将测试 BAI1 在促进体内吞噬方面是否提供独特的信号与冗余的信号。目标 2 重点关注凋亡细胞识别如何转化为抗炎细胞因子的产生，这是尚未完全了解的凋亡细胞清除的关键特征。我们将检验 BAI1-ELMO1 介导的信号传导有助于吞噬细胞的抗炎反应的假设。具体来说，我们将测试 ELMO1 和转录机制组件（我们在初步研究中发现的）之间的意外相互作用如何促进吞噬过程中的抗炎基因转录。我们将在组织炎症小鼠模型中使用缺乏 Elmo2（我们最近生成的）的小鼠在体内扩展这些研究。总的来说，我们期望这些研究能够提供有关体内细胞清除中通过 BAI1/Elmo1 信号通路进行信号传导的令人兴奋的新信息。由于 ELMO1 和 BAI1 表达的改变在基因上与人类炎症性疾病有关，因此拟议研究的结果可能与炎症性疾病的治疗干预相关。