Abnormal Energy Homeostasis in ALS

描述（由申请人提供）：这些研究的长期目的是确定纠正ALS的代谢异常是否会减缓神经变性过程的进展。特定目的-先前对ALS患者和运动神经元疾病小鼠模型的研究表明，能量摄入和消耗之间存在不平衡。关键的异常是基础代谢率的增加，这个问题在所有组织中都很明显，尤其是在肌肉中。这种能量摄入和消耗的不平衡在病理生理学上具有重要意义，因为通过给突变小鼠提供高脂肪、高热量的饮食，可以部分纠正这种不平衡，从而减缓疾病的进展。特异性目的：基因降低基础代谢率是否可以预防或减缓SOD突变小鼠的运动神经元疾病？瘦素- obr信号系统控制食物摄入和基础代谢率。我们将在ob/ob背景下产生表达G93A突变型人SOD的小鼠。ob基因座编码瘦素蛋白，ob/ob小鼠代谢低下（在其他代谢紊乱中）。我们将监测，随着时间的推移，力量，耐力，存活率，运动神经元数量和代谢参数。将研究两种饮食方案：1)动物将自由地获得食物，这导致ob/ob小鼠明显肥胖。这种情况在表达ob/ob背景突变的小鼠中发生的程度只能凭经验确定，这对运动神经元疾病的影响程度也只能凭经验确定。ob/ob的低代谢表型导致配对喂养的动物体重增加，但在自由获取食物的动物中发生的情况较少。这种喂养模式将由ob/ob引起的系统性低代谢改变与由瘦素- obr信号缺陷引起的贪食分离开来。主要方法/主要组织。我们将使用G93A SOD小鼠和ob/ob小鼠。将进行行为学、解剖学、生物化学和代谢研究。与神经肌肉疾病的关系。这些研究与所有运动神经元疾病直接相关。公共卫生相关性：该项目旨在将生物体的代谢与神经退行性疾病的易感性联系起来。如果食物消耗和代谢率与神经退行性疾病有关，那么新的干预形式（即饮食、运动、药理学）可能在治疗上有用。

DESCRIPTION (provided by applicant): The longterm of objective of these studies is to determine if correcting the metabolic abnormalities in ALS will slow the progression of the neurodegeneration process. Specific aim - Previous studies of patients with ALS and mouse models of motor neuron disease have demonstrated an imbalance between energy intake and expenditure. The key abnormality is increased basal metabolic rate a problem evident in all tissue, most significantly in muscle. This imbalance of energy intake and expenditure is pathophysiologically significant, since it's partial correction by providing mutant mice with a high fat, high calorie diet slows disease progression. Specific aim: Is the motor neuron disease of mutant SOD mice prevented or slowed by genetically reducing basal metabolic rate? The Leptin-ObR signaling system controls food intake and basal metabolic rate. We will generate mice that express G93A mutant human SOD in the ob/ob background. The ob locus encodes the protein leptin and ob/ob mice are hypometabolic (among other metabolic derangements). We will monitor, over time, strength, endurance, survival, motor neuron number and metabolic parameters. Two dietary regimens will be studied: 1) Animals will be given ad libitum access to food and this leads to marked obesity in the ob/ob mice. The extent to which this will occur in mice expressing mutant in the ob/ob background can only be determined empirically as is the extent to which this influences motor neuron disease, 2) Animals will be pair-fed. The hypometabolic phenotype of the ob/ob leads to weight gain in pair fed animals, but less than occurs in animals with ad libitum access to food. This feeding paradigm isolates systemic hypometabolic alterations engendered by the ob/ob from the hyperphagia incurred by defective leptin-ObR signaling. Primary methodology/principle organism. We will use the G93A SOD mouse and the ob/ob mouse. Behavioral, anatomical, biochemical and metabolic studies will be undertaken. Relationship to neuromuscular disease. These studies are directly relevant to all motor neuron disease. PUBLIC HEALTH RELEVANCE: This project aims to link metabolism of the organism with susceptibility to neurodegenerative diseases. If food consumption and metabolic rate are related to neurodegenerative disease then new forms of intervention (i.e., diet, exercise, pharmacology) may prove useful therapeutically.