The HH: A Large Cohort of Patients with Congenital Myopathies of Uncertain Etiology

HH：一大群患有病因不明的先天性肌病的患者

基本信息

批准号：
10214533
负责人：
Michael Fill
金额：
$ 48.32万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214533
关键词：
Adult Affect Affinity Agonist Anesthetics Biopsy Buffers CAV1 gene Caffeine Canada Cell Culture Techniques Cell physiology Cells Central Core Myopathy Chemical Stimulation Chronic Chronically Ill Clinic Clinical Clinical Trials Collaborations Complement Contracture Coupled Coupling Creatine Kinase Cultured Cells Cysteine Cytosol Dantrolene Data Defect Deformity Diagnosis Diagnostic Diagnostic tests Disease Disease Management Dose Electric Stimulation Etiology Event Exposure to Fiber Fingerprint Frequencies Future Genetic Genotype Gold Grant Halothane Heritability Histopathology Human Hypersensitivity Image Individual Inherited Intervention Investigation Ions Knowledge Laboratories Link Malignant hyperpyrexia due to anesthesia Measurement Measures Mechanics Medical Genetics Medical History Membrane Molecular Muscle Muscle Cramp Muscle Fibers Muscle function Muscle relaxants Mutation Myalgia Myopathy Names Normalcy Operative Surgical Procedures Outcome Parents Pathogenesis Pathogenicity Pathway interactions Patients Permeability Pharmaceutical Preparations Phenotype Physiology Play Population Predisposition Prevalence Process Property Protein Isoforms Proteins Protocols documentation Research Resources Rest Rhabdomyolysis RyR1 Ryanodine Receptors Sampling Sarcoplasmic Reticulum Serum Ships Signal Transduction Skeletal Muscle Specificity Stress Striated Muscles Structure Symptoms System Testing Therapeutic Therapeutic Intervention Time Underserved Population Variant Work base bone carvedilol clinical phenotype cohort congenital myopathy design disease phenotype exome experience extracellular indexing individual patient novel novel therapeutics prospective public health relevance receptor expression research clinical testing sensor tool triadin voltage

项目摘要

Project Summary Intracellular Ca signals reach great intensity in muscle, where they are key to the “Excitation- Contraction Coupling” (ECC) process. In striated muscles they are produced by a supramolecular assembly that we named the couplon, which crucially includes ryanodine receptors (RyRs), channels of the sarcoplasmic reticulum (SR). Multiple diseases arise from abnormal ECC; among them, the paradigmatic Malignant Hyperthermia is diagnosed by the “CHCT”, a conventional challenge with caffeine and halothane. In a 72- patient sample, we have found that roughly 20% tested positive, 40% were negative and 40% tested equivocally, meaning that they Hyper-reacted to Halothane, but not to caffeine. Clinical work found that these patients, which we call the “HH”, are sick, suffering from muscle pain, weakness, high sensitivity to stress, or heat, or statins, and experience rhabdomyolysis and other setbacks. This is in stark contrast with most MH- positive patients, who have a susceptibility to well-known triggers, but otherwise no active disease phenotype. Here, two physiology labs have teamed with the clinic that studies the greatest number of congenital non- dystrophic myopathies in the hemisphere (the MHIU) to propose a comprehensive study of approximately 300 patients. A detailed clinical and genetic picture of each tested patient will be matched by: (1) a cell-level quantification of Ca handling (from measurements of steady and stimulated Ca ion concentration in cytosol and SR, as well as steady and stimulated fluxes between these compartments in adult and cultured cells derived from patients’ biopsies), and (2) a matching molecular description, from measurements of function of single SR Ca release RyR1 channels derived from the patients. Many of these measurements will be the first done in human cells. The results will be interpreted in terms of “pathogenic pathways”, which track the causal chain, starting from a primary defect (e.g. an excessive tendency for RyR to open) to account for and predict the multiple changes that occur downstream. This mechanistic knowledge will then be used to devise therapeutic interventions, tailored rationally to offset the primary defect or the main drivers of the established pathogenic pathways. These may include steady changes in ion composition of the extracellular medium, the classic drug dantrolene and/or application of a large set of newly synthesized RyR-inhibiting drugs, carvedilol derivatives modified from the parent drug to eliminate its beta-blocking action. Among the novel derivatives, 34 were prescreened favorably in a RyR expression system. The best of these, identified based on affinity, efficacy and RyR-isoform specificity, will be applied to single human RyR1 channels, myotubes and myofibers; their outcomes will be compared to those of dantrolene and interpreted within the mechanistic context established in this project. The close bench-clinical correlation of our study makes it possible to tailor the design of potential therapeutic interventions (initially informed by the collective properties of the HH and MH cohorts) to the phenotype (molecular, cellular, or organismal) of individual patients. In future iterations, the top therapeutic paradigms will join clinical testing already going on at the MHIU. (Rev. 11/02/16)

项目概要细胞内 Ca 信号在肌肉中达到很高的强度，它们是“兴奋- 在横纹肌中，它们是由超分子组装产生的“收缩耦合”（ECC）过程。我们将其命名为耦合子，其中关键包括兰尼碱受体 (RyRs)，即肌浆通道网状细胞 (SR) 是由异常 ECC 引起的，其中典型的是恶性疾病；体温过高是通过“CHCT”诊断的，这是一种使用咖啡因和氟烷进行的传统测试，在 72-72 ℃下进行。患者样本中，我们发现大约 20% 检测呈阳性，40% 呈阴性，40% 检测呈阳性含糊其辞，这意味着他们对氟烷有过度反应，但对咖啡因没有反应。临床工作发现这些。患者，我们称之为“HH”，患有疾病，患有肌肉疼痛、虚弱、对压力高度敏感，或热或他汀类药物，并经历横纹肌溶解症和其他挫折，这与大多数 MH-形成鲜明对比。阳性患者，对已知的触发因素具有易感性，但没有活跃的疾病表型。在这里，两个生理学实验室与研究最多先天性非遗传性疾病的诊所合作。半球营养不良性肌病 (MHIU) 提议对大约 300 名患者进行全面研究每个测试患者的详细临床和基因图谱将通过以下方式进行匹配：(1) 细胞水平。 Ca 处理的量化（通过测量细胞质中稳定和受刺激的 Ca 离子浓度） SR，以及成体细胞和培养细胞衍生的这些区室之间的稳定和刺激通量 (2) 匹配的分子描述，来自单个 SR 功能的测量来自患者的 Ca 释放 RyR1 通道中的许多测量将是首次在体内完成。人类细胞的结果将根据追踪因果链的“致病途径”来解释，从主要缺陷（例如 RyR 过度打开的趋势）开始，解释并预测然后，下游发生的多种变化将被用来设计治疗方法。拦截，合理定制以抵消主要缺陷或已确定致病的主要驱动因素这些可能包括细胞外介质（经典药物）的离子组成的稳定变化。丹曲林和/或大量新合成的 RyR 抑制药物卡维地洛衍生物的应用在新型衍生物中，有 34 种是对母体药物进行修饰以消除其 β 阻滞作用。根据亲和力、功效和特性，在 RyR 表达系统中进行了有利的预筛选。 RyR-亚型特异性，将应用于单个人 RyR1 通道、肌管和肌纤维；结果将与丹曲林的结果进行比较，并在建立的机制背景下进行解释我们的研究与临床密切相关，使得定制潜在的设计成为可能。治疗干预措施（最初根据 HH 和 MH 队列的集体特性）个体患者的表型（分子、细胞或生物）在未来的迭代中，顶级治疗方法。范例将加入 MHIU 正在进行的临床测试（Rev. 11/02/2016）。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anaesthesia and neuromuscular disorders: what a neurologist needs to know.

麻醉和神经肌肉疾病：神经科医生需要了解什么。

DOI：
发表时间：
2020-10-27
期刊：
影响因子：
2.8
作者：
van den Bersselaar, Luuk R;Snoeck, Marc M J;Gubbels, Madelief;Riazi, Sheila;Kamsteeg, Erik;Jungbluth, Heinz;Voermans, Nicol C
通讯作者：
Voermans, Nicol C

A multi-dimensional analysis of genotype-phenotype discordance in malignant hyperthermia susceptibility.

恶性高热易感性基因型-表型不一致的多维分析。

DOI：
发表时间：
2020-12
期刊：
影响因子：
9.8
作者：
Ibarra Moreno, Carlos A;Kraeva, Natalia;Zvaritch, Elena;Figueroa, Lourdes;Rios, Eduardo;Biesecker, Leslie;Van Petegem, Filip;Hopkins, Philip M;Riazi, Sheila
通讯作者：
Riazi, Sheila

Untargeted metabolomics profiling of skeletal muscle samples from malignant hyperthermia susceptible patients.

对恶性高热易感患者的骨骼肌样本进行非靶向代谢组学分析。

DOI：
发表时间：
2021-06
期刊：
影响因子：
0
作者：
Bojko, Barbara;Vasiljevic, Tijana;Boyaci, Ezel;Roszkowska, Anna;Kraeva, Natalia;Ibarra Moreno, Carlos A;Koivu, Annabel;Wąsowicz, Marcin;Hanna, Amy;Hamilton, Susan;Riazi, Sheila;Pawliszyn, Janusz
通讯作者：
Pawliszyn, Janusz

Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia-Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability.

口服丹曲林治疗恶性高热敏感患者的肌病症状：一项关于不良反应和耐受性的 25 年回顾性队列研究。

DOI：
发表时间：
2023-03-01
期刊：
影响因子：
5.7
作者：
Ibarra Moreno, Carlos A;Kraeva, Natalia;Zvaritch, Elena;Jungbluth, Heinz;Voermans, Nicol C;Riazi, Sheila
通讯作者：
Riazi, Sheila

Skeletal Muscle Metabolic Dysfunction in Patients With Malignant Hyperthermia Susceptibility.

恶性高热易感性患者的骨骼肌代谢功能障碍。

DOI：
发表时间：
2017-08
期刊：
影响因子：
5.7
作者：
Thompson, Sara J;Riazi, Sheila;Kraeva, Natalia;Noseworthy, Michael D;Rayner, Tammy E;Schneiderman, Jane E;Cifra, Barbara;Wells, Greg D
通讯作者：
Wells, Greg D