Clinical and Non-Invasive Biomarkers of Myotonic Dystrophy

强直性肌营养不良的临床和非侵入性生物标志物

• 批准号: 10524478
• 负责人: Paloma Gonzalez-Perez
• 金额: $ 20.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524478
• 关键词: Address; Adult; Advisory Committees; Affect; Age; Agreement; Animal Disease Models; Architecture; Area; Atmosphere; Atrophic; Bilateral; Biological Markers; Biometry; Biopsy; Blinded; Brain; Clinical; Clinical Research; Clinical Trials; Collaborations; Computing Methodologies; DNA; Data; Development; Diagnosis; Disease; Disease Progression; Distal; Environment; Fatty acid glycerol esters; Fingers; Flexor; Forearm; Foundations; Frequencies; Future; General Hospitals; Genes; Goals; Heart; Image; In Vitro; Infiltration; Inherited; Leg; Limb structure; Longitudinal cohort; Magnetic Resonance Imaging; Massachusetts; Measurement; Measures; Mediating; Medical Research; Mentors; Monitor; Muscle; Muscle Fibers; Muscle Weakness; Muscle relaxation phase; Muscular Atrophy; Muscular Dystrophies; Myography; Myopathy; Myotonia; Myotonic Dystrophy; Neuromuscular Diseases; Neuromuscular conditions; Nucleotides; Ocimum basilicum; Organ; Pacemakers; Painless; Patients; Pattern; Persons; Phase; Physiologic pulse; Pilot Projects; Population; Positioning Attribute; Prevalence; Probability; Publications; RNA; Readiness; Relaxation; Reporting; Research; Research Personnel; Research Proposals; Resistance; Role; Sampling Biases; Scientist; Severity of illness; Skeletal Muscle; Specialist; Sum; System; Testing; Thick; Thigh structure; Time; Toxic effect; Training; Transcript; Translational Research; Ultrasonography; Validation; Visit; Walking; arm; autosome; candidate marker; career; career development; catalyst; data acquisition; design; disability; efficacy evaluation; electric impedance; grasp; lectures; medical schools; meetings; molecular marker; mouse model; muscle strength; musculoskeletal imaging; musculoskeletal ultrasound; mutant; neuromuscular; new technology; patient oriented research; patient response; portability; response; responsible research conduct; sex; time interval; tool; transcriptomics; ultrasound

PROJECT SUMMARY/ABSTRACT Myotonic dystrophy (dystrophia myotonica or DM) is the most common muscular dystrophy in adults (prevalence is 1/8,000) and an autosomal dominant multisystem disease caused by a CTG trinucleotide expansion in DMPK gene (DM type 1) or CCTG tetranucleotide expansion in CNBP gene (DM type 2). Such DNA expansions are responsible for the presence of toxic RNA molecules. Promising therapies are in current development to target these RNA transcripts; however, disease biomarkers to monitor disease activity and patient’s response to upcoming treatments are lacking. The proposed research focuses on identifying reliable and non-invasive biomarkers that serve to monitor the slow progression of DM muscle disease and that can be later used to also monitor response to upcoming treatments. This project not only addresses the need for muscle biomarkers in DM type 1 but also in DM type 2, that although less frequent, it is probably underdiagnosed. The applicant’s research strategy aims at investigating skeletal muscle MRI and ultrasound, and electrical impedance myography as monitoring disease biomarkers. The candidate’s research environment is ideal for the proposed project. The Massachusetts General Hospital (MGH) and Harvard Medical School provide an enriching and motivating academic atmosphere for trainees who have the opportunity to attend high-quality courses/lectures, collaborate with expert scientists and clinicians in the field of neuromuscular disorders and skeletal muscle imaging. The candidate’s mentoring team is composed by Dr. Thurman Wheeler and Dr. Seward Rutkove. Dr. Wheeler has been investigating DM for almost two decades by using in vitro and animal models of the disease, and more recently also disease biomarkers in patients’ biofluids. He has significantly contributed to advance the understanding of DM and he has become a renowned researcher in the field as shown in his numerous high-impact factor publications. Dr. Rutkove is a neuromuscular specialist with expertise on skeletal muscle ultrasound and electrical impedance myography, and with a successful clinical research career in the design and development of new technologies to better characterize neuromuscular diseases. As collaborator and consultant, Dr. Martin Torriani who directs the MGH Musculoskeletal Imaging Core and is an expert on skeletal muscle MRI. The advisory team will also contribute with expertise in applied computational methods and biostatistics (Dr. Hang Lee), and high-quality translational research in neuromuscular diseases and readiness for biomarker application into future clinical trials (Dr. Basil Darras and Dr. Sabrina Paganoni). The candidate’s training plan includes career development lectures (i.e Training in Responsible Conduct of Research), Harvard Catalyst courses (i.e Certificate in Applied Biostatistics) and attendance to scientific meetings (i.e Myotonic Dystrophy Foundation and Muscle Study Group). Candidate’s career goal is to transition towards an independent clinician-scientist position in the field of neuromuscular diseases with main focus on muscular dystrophies and patient-oriented research.

项目摘要/摘要 肌营养不良症（肌营养不良的肌动症或DM）是成人最常见的肌肉营养不良症 （患病率为1/8,000），是由CTG三核苷酸引起的常染色体显性多系统疾病 DMPK基因（DM 1型）或CCTG四核苷酸在CNBP基因（DM 2型）中的扩展。这样的 DNA膨胀是导致有毒RNA分子的存在。有希望的疗法目前是 开发这些RNA转录本；但是，疾病生物标志物监测疾病活动和 患者对即将进行的治疗的反应缺乏。拟议的研究重点是确定可靠的 和非侵入性生物标志物来监测DM肌肉疾病的缓慢进展，这可以是 后来还用来监视对即将进行的治疗的反应。这个项目不仅满足了需求 DM类型1中的肌肉生物标志物，但在DM类型2中也 诊断不足。申请人的研究策略旨在调查骨骼肌MRI和超声检查， 和电阻型的电阻为监测疾病生物标志物。候选人的研究 环境是拟议项目的理想选择。马萨诸塞州综合医院（MGH）和哈佛大学 医学院为拥有的学员提供了丰富而激励的学术氛围 有机会参加高质量课程/讲座，与该领域的专家科学家和临床医生合作 神经肌肉疾病和骨骼肌成像。候选人的心理团队由 瑟曼·惠勒（Thurman Wheeler）博士和苏德·鲁特科夫（Seward Rutkove）博士。惠勒博士一直在调查DM几乎两个 数十年来，使用该疾病的体外和动物模型，最近也是疾病生物标志物 患者的生物流体。他为促进对DM的理解做出了重大贡献，他已经成为 如他众多的高影响力因素出版物所示，该领域的著名研究人员。鲁特科夫博士是 神经肌肉专家，具有骨骼肌超声和电阻力的专业知识， 并在新技术的设计和开发方面取得了成功的临床研究职业 表征神经肌肉疾病。作为合作者和顾问，指挥MGH的马丁·托里亚尼（Martin Torriani）博士 肌肉骨骼成像核心，是骨骼肌MRI的专家。咨询团队也将 用应用计算方法和生物统计学（Hang Lee博士）和高质量的专业知识做出贡献 神经肌肉疾病的转化研究和生物标志物应用程序的准备 试验（Basil Darras博士和Sabrina Paganoni博士）。候选人的培训计划包括职业发展 讲座（即负责任的研究培训），哈佛催化剂课程（即应用​​证书 生物统计学）和参加科学会议（即肌营养不良基础和肌肉研究 团体）。候选人的职业目标是过渡到该领域的独立临床科学家职位 神经肌肉疾病主要关注肌肉营养不良和以患者为导向的研究。