Body Composition and Energy Utilization in Spinal Muscular Atrophy

描述（由申请人提供）：脊髓性肌萎缩症（SMA）是一种遗传性小儿神经肌肉疾病，以脊髓运动神经元丧失导致的进行性无力和肌肉萎缩为特征。SMA表现在临床范围内，从历史上预后不佳的极度虚弱的婴儿（werdnigi - hoffmann， SMA 1型）到轻度影响，活动的儿童和成人（Kugelberg-Welander， SMA 3型）。尽管缺乏有效的治疗方法，近年来积极的营养管理（包括胃造口放置）以及机械通气支持的广泛使用极大地改变了疾病的“自然史”。1型脊髓性肌萎缩症患儿的生存率得到了特别的提高。不幸的是，尽管营养和身体成分是SMA患者最佳临床管理中潜在重要的可改变因素，但几乎没有数据或同行评审的研究可用于告知这一领域的临床护理。我们建议使用最先进的方法和技术研究SMA儿童和成人的能量消耗、热量摄入（以及热量平衡）和身体成分。我们的目标是推进目前有限的理解营养在脊髓性肌萎缩。制定针对患者的饮食建议将对受影响的患者具有潜在的临床益处，并可能有意地改善SMA患者的生活。我们还将研究肌肉成像方法，如MRI和双能x线吸收仪，以及电阻抗肌图，作为SMA疾病进展的潜在生物标志物。疾病进展（和治疗效果）的生物标志物的开发对于加速早期临床试验至关重要。我的目标是建立一个临床研究工作，研究SMA患者的营养和身体成分，最终目的是通过改善临床护理来影响SMA患者和其他儿科神经肌肉疾病的功能和预后。为此，我正在通过纽约肥胖营养研究中心（NYONRC）和营养学，通过哥伦比亚大学欧文临床与转化研究所和人类营养研究所，与越来越多的同事合作，研究身体成分和能量消耗。我的建议包含了一个全面的指导和培训课程，其中包括：1)NYONRC的高级研究员Dympna Gallagher博士和儿科神经肌肉疾病资深研究员Darryl De Vivo博士的积极指导；2)通过NYONRC进行正式的教育研讨会、期刊俱乐部和实验室培训；3)通过营养研究所的课程活动，4)补充临床和临床研究职责；5)完成拟研究项目，并成功申请独立资助。

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a hereditary pediatric neuromuscular disease marked by progressive weakness and muscle atrophy resulting from the loss of spinal cord motor neurons. SMA presents across a clinical spectrum, ranging from extremely weak infants with a historically dismal prognosis (Werdnig-Hoffmann, SMA type 1) to mildly affected, ambulatory children and adults (Kugelberg-Welander, SMA type 3). Despite the absence of an effective therapy, aggressive nutritional management (including gastrostomy placement) along with widespread use of mechanical ventilatory support has greatly altered the "natural history" of the disease in recent years. Survival has been particularl improved among children with spinal muscular atrophy type 1. Unfortunately, although nutrition and body composition are a modifiable factors of potential importance in the optimal clinical management of patients with SMA, there is almost no data or peer- reviewed study available to inform this area of clinical care. We propose to study energy expenditure, caloric intake (and therefore caloric balance), and body composition, using state-of-the-art approaches and technology, among children and adults with SMA. We aim to advance the presently limited understanding of nutrition in spinal muscular atrophy. The development of patient- specific dietary recommendations would be of potential clinical benefit to affected patients, and could meaningfully improve the lives of people with SMA. We will also study muscle imaging approaches such as MRI and dual energy x-ray absorptiometry, and electrical impedance myography, for potential use as biomarkers of disease progression in SMA. The development of biomarkers of disease progression (and treatment effect) is critical in the acceleration of early stage clinical trials. My goal is to build a clinical research effort studying nutrition and body composition in SMA, with the ultimate aim of impacting function and outcome of patients with SMA and other pediatric neuromuscular diseases through improvements in clinical care. To this end, I am working with a growing network of colleagues in body composition and energy expenditure, through the New York Obesity Nutrition Research Center (NYONRC), and nutrition, through the Irving Institute for Clinical and Translational Research and Institute of Human Nutrition at Columbia University. My proposal incorporates a comprehensive mentoring and training curriculum that includes: 1) active mentorship from Dr. Dympna Gallagher, Ph.D., a senior researcher with the NYONRC, and Dr. Darryl De Vivo, M.D., an experienced researcher in pediatric neuromuscular disease; 2) formal educational seminars and journal clubs and laboratory training through the NYONRC; 3) coursework activities through the Institute of Nutrition, 4) complementary clinical and clinical research responsibilities; and 5) completion of the proposed research project leading to successful application for independent funding. PUBLIC HEALTH RELEVANCE: We aim to advance evidence-based nutritional management in spinal muscular atrophy (SMA), an untreatable hereditary pediatric neuromuscular disease marked by the loss of spinal cord motor neurons. We will study the relationship between disease severity, body composition and energy expenditure with the goal of informing clinical management and the potential role of nutritional modulation to affect the natural course of the disease. We will also study muscle imaging and electrical impedance as potential biomarkers of disease progression; the development of such biomarkers is of critical importance in the acceleration of clinical trials in SMA.