Body Composition and Energy Utilization in Spinal Muscular Atrophy

描述（由申请方提供）：脊髓性肌萎缩症（SMA）是一种遗传性儿科神经肌肉疾病，其特征为脊髓运动神经元缺失导致的进行性无力和肌肉萎缩。SMA存在于临床谱中，从极虚弱的婴儿（既往预后不良）（Werdnig-Hoffmann，SMA 1型）到轻度受累的可走动儿童和成人（Kugelberg-Welander，SMA 3型）。尽管缺乏有效的治疗，积极的营养管理（包括胃造口术）沿着广泛使用的机械辅助支持，极大地改变了近年来疾病的“自然史”。1型脊髓性肌萎缩症儿童的生存率得到了特别改善。不幸的是，尽管营养和身体成分是SMA患者最佳临床管理中具有潜在重要性的可改变因素，但几乎没有数据或同行评议研究可用于告知该临床护理领域。我们建议使用最先进的方法和技术，在SMA儿童和成人中研究能量消耗、热量摄入（以及热量平衡）和身体组成。我们的目标是促进目前有限的了解营养脊髓性肌萎缩症。制定患者特定的饮食建议将对受影响患者具有潜在的临床获益，并可显著改善SMA患者的生活。我们还将研究肌肉成像方法，如MRI和双能X线吸收测定法，以及电阻抗肌电图，作为SMA疾病进展的生物标志物的潜在用途。疾病进展（和治疗效果）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研究SMA营养和身体成分的临床研究工作，最终目的是通过改善临床护理来影响SMA和其他儿科神经肌肉疾病患者的功能和结局。为此，我正在通过纽约肥胖营养研究中心（NYONRC）与越来越多的身体成分和能量消耗方面的同事合作，并通过哥伦比亚大学的欧文临床和转化研究所和人类营养研究所与营养学合作。我的建议包括一个全面的指导和培训课程，其中包括：1）积极的导师从博士丁普纳加拉格尔，博士，NYONRC的高级研究员和医学博士Darryl De Vivo，在儿科神经肌肉疾病的经验丰富的研究人员; 2）通过NYONRC正式的教育研讨会和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的责任;和5）完成拟议的研究项目，导致成功申请独立的资金。 公共卫生相关性：我们的目标是推进脊髓性肌萎缩症（SMA）的循证营养管理，脊髓性肌萎缩症是一种无法治疗的遗传性儿科神经肌肉疾病，其特征是脊髓运动神经元的丧失。我们将研究疾病严重程度，身体成分和能量消耗之间的关系，目的是为临床管理提供信息，以及营养调节对影响疾病自然病程的潜在作用。我们还将研究肌肉成像和电阻抗作为疾病进展的潜在生物标志物;这些生物标志物的开发对于加速SMA临床试验至关重要。

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.