Obesity as a Driver of Inflammation and Brain Volume Loss in Pediatric Multiple Sclerosis

肥胖是小儿多发性硬化症炎症和脑容量减少的驱动因素

• 批准号: 10519109
• 负责人: James N. Brenton
• 金额: $ 19.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10519109
• 关键词: Acceleration; Adipocytes; Adipose tissue; Adolescence; Adult; Affect; Age; Animal Model; Atrophic; Award; Biological; Biological Markers; Body mass index; Brain; CNS autoimmune disease; Categories; Central Nervous System; Child; Childhood; Clinical; Clinical Research; Cohort Studies; Conduct Clinical Trials; Cross-Sectional Studies; Data; Data Set; Demyelinations; Development; Development Plans; Diagnosis; Disease; Disease Progression; Epidemic; Exhibits; Failure; Fasting; Funding; Future; Goals; Growth; Health; Image; Immune; Immune response; Immune system; Immunotherapy; Inflammation; Inflammatory; Injury; International; Intervention Studies; Leptin; Lesion; Life; Light; Link; Longitudinal cohort study; Magnetic Resonance Imaging; Measures; Mediating; Mentors; Modeling; Modification; Molecular Weight; Multi-site clinical study; Multiple Sclerosis; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neurologist; Neurons; Non obese; Obesity; Only Child; Outcome; Overweight; Patients; Pediatric Hospitals; Persons; Philadelphia; Prospective Studies; Protein Isoforms; Publishing; Radiology Specialty; Research; Research Methodology; Research Personnel; Risk; Risk Factors; Role; Sampling; Science; Scientist; Serology; Serum; Severities; Severity of illness; Techniques; Therapeutic; Time; Training; United States National Institutes of Health; Weight; Work; adipokines; adiponectin; brain volume; career development; cell injury; cerebral atrophy; cohort; cytokine; design; disability; experience; gray matter; immunoregulation; modifiable risk; neurofilament; neuroimaging; novel; obesity in children; overweight child; pediatric multiple sclerosis; pediatric patients; recruit; repository; sex; tool; young adult

PROJECT SUMMARY/ABSTRACT Dr. Brenton is a pediatric neurologist whose long-term goal is to become an expert in multiple sclerosis (MS) therapeutics and risk factor modification. The training and mentored research experience proposed will enable him to develop expertise in: 1) the conduct of multi-centered clinical studies, 2) use of MRI as a research tool, and 3) obesity science. Dr. Brenton has assembled an expert team of mentors/advisors to help him. Dr. Karen Johnston (primary mentor) is a highly-successful international expert in clinical trial conduct, Dr. Myla Goldman (co-mentor) is a nationally-recognized expert in MS clinical research, and Dr. Brenda Banwell (co-mentor) is a world-expert in pediatric MS clinical research. Dr. Brenton will take courses pertinent to research methodology, the study of obesity and its relevant biomarkers, and the application of neuroimaging techniques in clinical research. He will also spend 5 weeks at the Children’s Hospital of Philadelphia to gain hands-on experience with Dr. Banwell in the use of neuroimaging as a biomarker for pediatric MS outcomes. Children with MS, the most common autoimmune disease of the central nervous system (CNS), experience failure of age-expected brain growth followed by progressive brain atrophy during adolescence. These children often develop physical and neurocognitive disability at a young age. Childhood obesity is an established risk determinant for pediatric MS, however, the impact of persisting obesity on MS disease course is unknown. In non-MS children and young adults, obesity (a national health epidemic) associates with progressive brain volume loss. In adults with MS, greater levels of obesity are associated with significantly reduced normalized gray matter volumes. This is important, as gray matter atrophy is directly linked with progressive disability in MS. The impact of obesity in children with MS has not been studied and the implications of this are particularly important in a pediatric patient – where the negative impact of obesity on the CNS may exert an even greater detrimental effect on a brain that is still undergoing development. We will conduct a cross-sectional, multi-center cohort study to determine the relationship between obesity and biomarkers of 1) inflammation (measured radiologically by T2-hyperintense inflammatory lesion volumes & serologically by adipocyte-derived cytokines) and 2) neurodegeneration (measured radiologically by whole brain volumetrics & serologically by neurofilament light chain). This study will help define the role of obesity in pediatric MS disease and will set the stage for future intervention studies aimed at modifiable risk factors in MS. Upon completion of this award, Dr. Brenton will be one of the only child neurologists in the world with formal training in pediatric MS in combination with training in obesity science and MS neuroimaging. His proposal represents the first and only prospective study evaluating the role of obesity on pediatric MS disease severity at presentation. This K23 will provide the necessary data and experience to inform future studies, and he will be well-poised to apply for future R01 funding as an independent, collaborative clinician-scientist.

项目总结/摘要 布伦顿博士是一名儿科神经学家，他的长期目标是成为多发性硬化症的专家 (MS)治疗和风险因素的修改。拟议的培训和指导研究经验将 使他能够发展以下方面的专业知识：1）进行多中心临床研究，2）使用MRI作为 研究工具，和3）肥胖科学。布伦顿博士组建了一个专家团队的导师/顾问，以帮助 他Karen约翰斯顿博士（主要导师）是一位非常成功的国际临床试验专家。 Myla Goldman（共同导师）是全国公认的MS临床研究专家，Brenda Banwell博士 （共同导师）是儿科MS临床研究的世界专家。布伦顿博士将学习与 研究方法、肥胖及其相关生物标志物的研究、神经影像学的应用 临床研究中的技术。他还将在费城儿童医院度过5周， Banwell博士在使用神经影像学作为儿科MS结局生物标志物方面的实践经验。 MS儿童是中枢神经系统（CNS）最常见的自身免疫性疾病， 经历年龄预期的脑生长失败，随后在青春期进行性脑萎缩。 这些儿童往往在很小的时候就出现身体和神经认知障碍。儿童肥胖是一种 儿童MS的风险决定因素，然而，持续肥胖对MS病程的影响 不明在非MS儿童和年轻人中，肥胖（一种全国性的健康流行病）与以下因素有关： 进行性脑容量丧失在患有MS的成年人中，更高水平的肥胖与 减少了正常化的灰质体积。这一点很重要，因为灰质萎缩与 肥胖对MS儿童的影响尚未研究， 这一点在儿科患者中尤其重要，因为在儿科患者中，肥胖对 CNS可能对仍在发育中的大脑产生更大的有害影响。 我们将进行一项横断面、多中心队列研究，以确定 肥胖和1）炎症（通过T2高信号炎性病变放射学测量）的生物标志物 体积和血清学上通过脂肪细胞衍生的细胞因子）和2）神经变性（通过放射学上测量， 全脑体积测定法和血清学上通过神经丝轻链测定）。这项研究将有助于确定 儿童MS疾病中的肥胖，并将为未来旨在改变风险的干预研究奠定基础 在这个奖项完成后，布伦顿博士将是世界上唯一的儿童神经学家之一。 接受过儿科MS的正式培训，并接受过肥胖科学和MS神经成像方面的培训。他 该提案是第一个也是唯一一个评估肥胖对儿童MS疾病作用的前瞻性研究 介绍时的严重程度。K23将为今后的研究提供必要的数据和经验， 他将作为一名独立的、合作的临床科学家申请未来的R 01资助。