Mitokines as new targets for fatigue induced by mitochondrial stress

线粒体因子作为线粒体应激引起的疲劳的新靶点

• 批准号: 10598758
• 负责人: Robert Dantzer
• 金额: $ 44.55万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598758
• 关键词: Address; Adenosine Triphosphate; Adipose tissue; Anorexia; Applications Grants; Attention; Attenuated; Behavior; Behavior Therapy; Behavioral; Blood Circulation; Body Weight; Brain; Cachexia; Cell Nucleus; Cells; Cellular Stress; Cholecystokinin; Chronic; Chronic Disease; Cisplatin; Communication; Complex; Coupled; Cytotoxic agent; Data; Development; Distress; Eating; Endogenous Factors; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; FDA approved; Family; Fatigue; Feeling; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Functional disorder; GDF15 gene; General Population; High Prevalence; Homeostasis; Hormonal; Impairment; Implant; Individual; Inflammation; Intake; Intervention; Knock-out; Knowledge; Lead; Life; Lipopolysaccharides; Liver; Macronutrients Nutrition; Malignant Neoplasms; Measurement; Measures; Mediating; Medical; Metabolic; Mitochondria; Mitochondrial Diseases; Molecular; Motivation; Mus; Muscle; Neurons; Nutrient; Organ; Organelles; Oxidative Phosphorylation; Pathologic; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Play; Poison; Prevalence; Process; Proteins; Recovery; Regulation; Rewards; Role; Running; Signal Transduction; Site; Skeletal Muscle; Stress; Structure; Structure of area postrema; Symptoms; Testing; Time; Toxin; Tunicamycin; Virus Diseases; Wild Type Mouse; Work; analog; antagonist; brain tissue; cancer cachexia; carbohydrate metabolism; chemotherapy; druggable target; endoplasmic reticulum stress; exhaustion; experience; experimental study; fibroblast growth factor 21; hindbrain; lipid metabolism; mitochondrial dysfunction; muscle strength; negative affect; neurotrophic factor; neutralizing monoclonal antibodies; novel therapeutics; osmotic minipump; paracrine; pathogen; pre-clinical; prevent; primary outcome; receptor; receptor expression; response; secondary outcome; sex; social; subcutaneous; tool; two-dimensional

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.

项目摘要/摘要 疲劳是患者经历的最常见和破坏性的症状之一。它存在于大约一个 在普通人群中，每五个人中就有一个，其患病率急剧上升，达到或超过50%， 在癌症和病毒感染等几种疾病中。导致疲劳的具体机制 在很大程度上仍然不为人知。因此，目前还没有针对这种情况的机制指导疗法。虽然 炎症通常被认为是疲劳的主要原因，它并不总是出现在许多情况下 慢性疲劳。另一种机制是线粒体功能障碍，其关键作用就是证明 线粒体在能量代谢中的作用以及这些细胞器对毒素和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特征并不令人惊讶，但仍然缺少的是 是如何在代谢活跃的外周器官中由线粒体应激引起的能量代谢不足 传递到大脑，产生疲劳感及其行为表现。有丝分裂素，如 GDF15和FGF21是这种通信的候选，因为它们被产生为旁分泌和 在线粒体应激条件下维持能量动态平衡的激素因素。来检验我们的假设 有丝分裂素通过作用于大脑而引起疲劳，我们将评估外源性给予GDF15的能力 和FGF21诱导疲劳并研究它们的受体机制(目标1)，然后确定它们的 作为内源性因素对线粒体应激的反应，释放的内源性因素介导了在此过程中发展起来的疲劳 条件(目标2)。在这两个目标中，我们将测量疲劳及其激励成分(“能”和“将” 疲劳的方面)，通过减少自愿活动和减少从事努力行为以获得 奖励。用于研究GDF15作用的工具包括长效形式的GDF15和中和剂 靶向其受体GFra的单抗。此外，我们将使用化学遗传方法来针对 CCK或TH在后脑胶质细胞中表达神经元，以确定其中枢作用部位。这个 用于研究FGF21作用的工具包括FGF21的类似物LY2405319，通过皮下给药 植入渗透性微泵和-klotho的多肽拮抗剂，FGF21的必需辅助受体 受体，这将是外周或中枢给药。线粒体应激将由以下因素引起 顺铂是化疗中使用的一种细胞毒剂，衣霉素是一种有毒化合物，会导致 未折叠的蛋白质反应和脂多糖。它们都能诱导GDF15和FGF21的释放。 线粒体应激的重要性将通过比较野生型小鼠和Tfam+/-小鼠进行比较 线粒体不稳定，应对顺铂的疲劳诱导作用更加敏感。这项临床前研究 该项目应该允许我们确定是否产生的有丝分裂因子GDF15和FGF21是对 线粒体应激通过作用于大脑而导致疲劳。预期的结果应该为进一步 描绘介导疲劳的神经网络，并识别治疗疲劳的可用药靶点。