Analysis of the biological roles of the vertebrate-specific, ovarian tumor (OTU) domain Fam105a protein

脊椎动物特异性卵巢肿瘤 (OTU) 结构域 Fam105a 蛋白的生物学作用分析

• 批准号: RGPIN-2020-06225
• 负责人: Cordes, Sabine
• 金额: $ 3.64万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=718268
• 关键词: Analysis; biological; roles; vertebrate; specific

Inflammatory signals emanating from the brain or distant organs can have considerable impacts on the developing and adult nervous system. For example, in rodents and primates, severe intestinal infections can activate the maternal immune system and cause behavioral and brain abnormalities in the resulting offspring. Further underscoring the complexity of neuroimmune crosstalk: both anti-viral responses and normal neuronal differentiation increase expression of immune signaling molecules called type I interferons, and some IFNs themselves can halt or impair neural stem cell proliferation. Mitochondria play roles in cell metabolism, responses to infectious agents and in immune and nervous system function. Cells regulate mitochondrial numbers by mitophagy. Some immune cells, such as for example, macrophages, use mitophagy to shift their metabolism and thereby their inflammatory state. Macrophages provide an ideal system for analyzing the interplay between mitophagy, cell state, inflammation and responses to infections. Macrophages can be classified into two groups: Pro-inflammatory, classically activated (M1) macrophages help eliminate infections. Atypically activated (M2) macrophages are judged anti-inflammatory and promote tissue repair. Induction of mitophagy and a shift towards glycolysis occurs during pro-inflammatory M1 macrophage activation. Recently we obtained evidence that the Ovarian Tumor (OTU) domain protein Fam105a/OtulinL may regulate mammalian mitophagy and be involved in immune and directly or indirectly nervous system homeostasis. FAM105A interacts with proteins known to regulate mitophagy. Moreover, we observed that mice lacking Fam105a show evidence of immune and nervous system dysfunction. Thus, we hypothesize that Fam105a regulates mammalian mitophagy and normally dampens innate immune activation. In its absence, nervous system dysfunction arises due to primary effects of disrupted mitochondrial dynamics in neurons or secondary consequences of (auto)-inflammation occurring in other regions of the body. To address this we will analyze the role of Fam105a in mitochondrial dynamics in bone marrow-derived macrophages (BMDMs) from mice lacking Fam105a with Drs. Angus McQuibban (UofT) and Andrea Jurisicova (LTRI).We will also analyze the roles of Fam105a in induction of M1/M2 states in macrophages and in anti-viral responses with Dr. John Brumell (HSC). We will determine whether losing Fam105a in nerves themselves causes behavioural abnormalities or whether inflammation in other regions of the body contributes to brain and behavioural abnormalities. These analyses will provide a new avenue for understanding the neuroimmune axis and the interactions between genetics, environmental challenges (i.e. infectious agents) and physiologic state (e.g. pregnancy) that shape mammalian neurodevelopment and behavior.

从大脑或远处器官发出的炎症信号可能对发育和成人神经系统产生相当大的影响。例如，在啮齿动物和灵长类动物中，严重的肠道感染会激活母体免疫系统，并导致后代的行为和大脑异常。进一步强调了神经免疫串扰的复杂性：抗病毒反应和正常的神经元分化都会增加称为I型干扰素的免疫信号分子的表达，并且一些IFN本身可以停止或损害神经干细胞增殖。 线粒体在细胞代谢、对感染因子的反应以及免疫和神经系统功能中发挥作用。细胞通过线粒体自噬调节线粒体数量。一些免疫细胞，例如巨噬细胞，使用线粒体自噬来改变它们的代谢，从而改变它们的炎症状态。巨噬细胞为分析线粒体自噬、细胞状态、炎症和感染反应之间的相互作用提供了一个理想的系统。巨噬细胞可分为两组：促炎性，经典激活（M1）巨噬细胞有助于消除感染。非典型活化（M2）巨噬细胞被判定为抗炎并促进组织修复。在促炎性M1巨噬细胞活化过程中发生线粒体自噬的诱导和糖酵解的转变。 近年来，我们发现卵巢肿瘤（Ovarian Tumor，OTU）结构域蛋白Fam 105 a/OtulinL可能参与哺乳动物的线粒体自噬，并直接或间接参与免疫和神经系统的稳态调节。FAM 105 A与已知调节线粒体自噬的蛋白质相互作用。此外，我们观察到缺乏Fam 105 a的小鼠表现出免疫和神经系统功能障碍的证据。 因此，我们假设Fam 105 a调节哺乳动物的线粒体自噬，并通常抑制先天免疫激活。 在其不存在的情况下，神经系统功能障碍是由于神经元中线粒体动力学破坏的主要影响或身体其他区域中发生的（自身）炎症的次要后果而引起的。 为了解决这个问题，我们将与安格斯McQuibban博士（UofT）和Andrea Jurisicova博士（LTRI）一起分析Fam 105 a在缺乏Fam 105 a的小鼠骨髓源性巨噬细胞（BMDM）线粒体动力学中的作用。我们还将与John Brumell博士（HSC）一起分析Fam 105 a在诱导巨噬细胞M1/M2状态和抗病毒应答中的作用。我们将确定神经本身失去Fam 105 a是否会导致行为异常，或者身体其他区域的炎症是否会导致大脑和行为异常。 这些分析将为理解神经免疫轴以及遗传学、环境挑战（即感染因子）和生理状态（例如妊娠）之间的相互作用提供新的途径，这些因素塑造了哺乳动物的神经发育和行为。