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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要强直性肌营养不良（肌强直性营养不良或 DM）是成人中最常见的肌营养不良（患病率为 1/8,000）以及由 CTG 三核苷酸引起的常染色体显性多系统疾病 DMPK 基因中的扩增（DM 1 型）或 CNBP 基因中的 CCTG 四核苷酸扩增（DM 2 型）此类。 DNA 扩增是导致有毒 RNA 分子存在的原因，目前有前景的治疗方法。然而，开发针对这些RNA转录本的疾病生物标志物来监测疾病活动和患者对即将到来的治疗缺乏反应。拟议的研究重点是确定可靠的治疗方法。以及非侵入性生物标志物，用于监测 DM 肌肉疾病的缓慢进展，并且可以后来还用于监测对即将到来的治疗的反应，该项目不仅满足了对治疗的需求。 1 型 DM 和 2 型 DM 中的肌肉生物标志物，虽然频率较低，但可能申请人的研究策略旨在调查骨骼肌 MRI 和超声波，和电阻抗肌电图作为监测疾病生物标志物。麻省总医院 (MGH) 和哈佛大学的环境非常适合该项目。医学院为具有以下能力的学员提供了丰富且激励人心的学术氛围有机会参加高质量的课程/讲座，与该领域的专家科学家和勇士合作神经肌肉疾病和骨骼肌成像的候选人的指导团队由以下人员组成。 Thurman Wheeler 博士和 Seward Rutkove 博士近两年来一直在研究 DM。几十年来，人们通过使用该疾病的体外和动物模型，以及最近的疾病生物标志物他为增进对 DM 的理解做出了重大贡献，他已成为一名糖尿病专家。 Rutkove 博士是该领域的著名研究员，他的众多高影响因子出版物表明了这一点。神经肌肉专家，具有骨骼肌超声和电阻抗肌电描记方面的专业知识，并在新技术的设计和开发方面拥有成功的临床研究生涯，以更好地作为合作者和顾问，麻省总医院 (MGH) 主任 Martin Torriani 博士研究了神经肌肉疾病的特征。肌肉骨骼成像核心，也是骨骼肌 MRI 方面的专家。贡献应用计算方法和生物统计学方面的专业知识（Hang Lee 博士）和高质量神经肌肉疾病的转化研究以及生物标志物应用于未来临床的准备试验（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（即负责任的研究行为培训）、Harvard Catalyst 课程（即应用证书生物统计学）和参加科学会议（即强直性肌营养不良基金会和肌肉研究候选人的职业目标是过渡到该领域的独立临床医生科学家职位。神经肌肉疾病的研究，主要关注肌肉营养不良和以患者为导向的研究。