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 疲劳是患者最常见和最破坏性的症状之一。它存在于大约一个 在普通人群中的五个人中，其患病率急剧增加，至50％以上， 在癌症和病毒感染等几种医疗状况下。负责疲劳的特定机制 仍然在很大程度上未知。因此，没有针对这种情况的机制引导疗法。虽然 炎症通常是疲劳的主要原因，在许多情况下并不总是存在 慢性疲劳。另一种机制是线粒体功能障碍，这是由关键作用证明 能量代谢中的线粒体以及这些细胞器对由毒素和 病原体。虽然疲劳是线粒体疾病的标志并不奇怪，但仍缺少的东西 是如何在代谢活性周围器官中由线粒体应激引起的能量代谢的缺乏 被传输到大脑，引起疲劳的感觉及其行为表达。诸如 GDF15和FGF21是进行旁分泌和旁分泌产生的候选者 在线粒体胁迫条件下维持能量体内稳态的激素因素。检验我们的假设 有丝分裂的作用在大脑中诱导疲劳，我们将评估外源给药GDF15的能力 和FGF21在确定是否是否诱导疲劳和研究其受体机制（AIM 1） 释放作为响应线粒体应力的内源性因素，介导了在此中遇到的疲劳 条件（目标2）。在这两个目标中，我们都将衡量疲劳及其动机成分（“罐头”和“意志” 疲劳的各个方面）通过减少自愿活动和降低有效行为以获得A 报酬。用于研究GDF15作用的工具包括GDF15的长效形式和中和 靶向其受体GFRAL的单克隆抗体。另外，我们将使用靶向的化学发生方法 GFRAL中包含的CCK或Th在后脑中表达神经元以识别其中心作用部位。这 用于研究FGF21作用的工具包括通过皮下施用的FGF21，LY2405319的类似物 植入的渗透微型蛋白酶和fgf21的强制性共受体的肽拮抗剂 受体将在外围或中央施用。线粒体应力将由 施用顺铂是一种用于化学疗法的细胞毒性剂，衣霉素，一种有毒化合物，影响 展开的蛋白质反应和脂多糖。它们都诱导GDF15和FGF21的释放。 通过将野生型小鼠与具有的TFAM +/-小鼠进行比较，将检查线粒体应力的重要性 线粒体不稳定性，应对顺铂的疲劳作用更敏感。这个临床前 项目应允许我们确定响应于 线粒体应力通过在大脑中作用会诱导疲劳。预期的结果应该为进一步铺平道路 介导疲劳的神经元网络的描述和可药物治疗疲劳的鉴定。