Mitokines as new targets for fatigue induced by mitochondrial stress

项目概要/摘要 疲劳是患者经历的最常见和最具破坏性的症状之一。它存在于大约一个 在一般人群中，五个人中就有一个，其患病率急剧增加，高达50%以上， 在几种医疗条件下，如癌症和病毒感染。造成疲劳的具体机制 仍然在很大程度上未知。因此，对于这种情况没有机制指导的治疗。虽然 炎症通常被认为是疲劳的主要原因，但它并不总是存在于许多情况下， 慢性疲劳另一种机制是线粒体功能障碍，这一点可以通过以下关键作用来证明： 线粒体在能量代谢中的作用以及这些细胞器对毒素引起的细胞应激的敏感性， 病原体虽然疲劳是线粒体疾病的标志并不奇怪，但仍然缺少的是 是如何在代谢活跃的外周器官中， 被传递到大脑，引起疲劳的感觉及其行为表现。线粒体因子，如 GDF 15和FGF 21是这种通信的候选者，因为它们作为旁分泌和旁分泌两者产生。 在线粒体应激条件下维持能量稳态的激素因子。为了验证我们的假设 我们将评估外源性给予GDF 15的能力 和FGF 21诱导疲劳，并研究其受体机制（目的1），然后再确定其是否 作为响应线粒体应激的内源性因子的释放介导了在这种情况下发展的疲劳。 条件（目标2）。在这两个目标中，我们将测量疲劳及其动机成分（“能够”和“意愿”）。 疲劳方面）通过减少自愿活动和降低参与努力行为的能力来获得 奖励用于研究GDF 15作用的工具包括GDF 15的长效形式和中和剂。 针对其受体的单克隆抗体GFRAL。此外，我们将使用化学遗传学方法靶向 CCK或TH中所含的GFRAL表达神经元在后脑，以确定其中央网站的行动。的 用于研究FGF 21作用的工具包括通过皮下给药的FGF 21类似物LY 2405319， 植入的渗透压微型泵，以及FGF 21的专性共受体--klotho的肽拮抗剂 受体，其将被外周或中枢施用。线粒体应激将由 施用顺铂，一种用于化疗的细胞毒性剂，衣霉素，一种毒性化合物， 未折叠蛋白质反应和脂多糖。它们都诱导GDF 15和FGF 21的释放。 线粒体应激的重要性将通过将野生型小鼠与具有以下特征的Tfam+/-小鼠进行比较来检查： 线粒体的不稳定性，并且应该对顺铂的疲劳诱导作用更敏感。本临床前 该项目应该允许我们确定是否有丝分裂因子GDF 15和FGF 21产生的反应， 线粒体应激通过作用于大脑而引起疲劳。预期的结果应该为进一步的工作铺平道路。 描绘介导疲劳的神经元网络和用于鉴定治疗疲劳的可用药靶点。

Project Summary/Abstract Fatigue is one of the most common and disruptive symptoms experienced by patients. It is present in about one out of five individuals in the general population, and its prevalence increases dramatically, up to and above 50%, in several medical conditions such as cancer and viral infections. The specific mechanisms responsible for fatigue remain largely unknown. Consequently, there are no mechanism-guided therapies for this condition. Although inflammation is often presented as a primary cause of fatigue, it is not always present in many instances of chronic fatigue. An alternative mechanism is mitochondrial dysfunction, as attested by the pivotal role of mitochondria in energy metabolism and the sensitivity of these organelles to cellular stress caused by toxins and pathogens. While it is not surprising that fatigue is the hallmark of mitochondrial diseases, what is still missing is how the deficit in energy metabolism caused by mitochondrial stress in metabolically active peripheral organs is transmitted to the brain to give rise to the feeling of fatigue and its behavioral expression. Mitokines such as GDF15 and FGF21 are candidates for such a communication as they are produced as both paracrine and hormonal factors to maintain energy homeostasis in conditions of mitochondrial stress. To test our hypothesis that mitokines induce fatigue by acting in the brain we will assess the ability of exogenously administered GDF15 and FGF21 to induce fatigue and study their receptor mechanisms (Aim 1) before determining whether their release as endogenous factors in response to mitochondrial stress mediates the fatigue that develops in this condition (Aim 2). In both aims, we will measure fatigue and its motivational component (the “can” and “will” aspects of fatigue) by decreased voluntary activity and reduced ability to engage in effortful behavior to obtain a reward. The tools used to study the role of GDF15 include a long-acting form of GDF15 and a neutralizing monoclonal antibody targeting its receptor, GFRAL. In addition, we will use chemogenetic approaches targeting CCK or TH contained in GFRAL expressing neurons in the hindbrain to identify its central site of action. The tools used to study the role of FGF21 include an analog of FGF21, LY2405319 administered via subcutaneously implanted osmotic minipumps, and a peptide antagonist of -klotho, the obligatory co-receptor of FGF21 receptors, that will be administered peripherally or centrally. Mitochondrial stress will be induced by administration of cisplatin, a cytotoxic agent used in chemotherapy, tunicamycin, a toxic compound that induces the unfolded protein response, and lipopolysaccharide. They all induce the release of both GDF15 and FGF21. The importance of mitochondrial stress will be checked by comparing wild type mice to Tfam+/- mice that have mitochondrial instability and should be more sensitive to the fatigue inducing effects of cisplatin. This preclinical project should allow us to determine whether the mitokines GDF15 and FGF21 that are produced in response to mitochondrial stress induce fatigue by acting in the brain. The expected results should pave the way for further delineation of the neuronal network mediating fatigue and for identification of druggable targets to treat fatigue.