Heterozygous MH knock-in mice model Human MH susceptibility
杂合 MH 敲入小鼠模型 人类 MH 易感性
基本信息
- 批准号:7436116
- 负责人:
- 金额:$ 21.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-04-01 至 2011-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffectBioinformaticsBiological MarkersBiopsy SpecimenBirthBlood ScreeningBlood specimenCalciumCellsCentral Core MyopathyClinicalCollaborationsContractureCoupledCouplingDantroleneDataDiagnostic testsDisease susceptibilityFunctional disorderFutureGene Expression ProfileGeneticGenotypeGoalsHalothaneHomeostasisHot SpotHumanIn VitroInvasiveKnock-in MouseLogisticsMalignant hyperpyrexia due to anesthesiaMarinesMembraneModelingMolecularMusMuscleMuscle FibersMutationMyopathyPathologyPathway interactionsPatientsPhenotypePhysiologicalPredispositionPrincipal InvestigatorProcessPropertyRNAReceiver Operating CharacteristicsRegression AnalysisRestReverse Transcriptase Polymerase Chain ReactionRyR1Ryanodine Receptor Calcium Release ChannelSamplingScreening procedureSensitivity and SpecificitySeveritiesSignal TransductionSkeletal systemSpecificityStressTestingWhole Bloodbasebench to bedsidecongenicdesignhuman diseasein vivomouse modelperipheral bloodprograms
项目摘要
The long-term goal of Project 1 is to define the mechanisms responsible for the ryanodine receptor (RyR1)
myopathies, malignant hyperthermia and central core disease (MH/CCD). Our immediate objectives are to
create suitable models for human disease in mice and use them to study how mutations of RyR1 alter
intracellular Ca2+ homeostasis and to create a noninvasive diagnostic test for MH that has a high degree of
specificity and sensitivity.
HYPOTHESIS I: Heterozygous MH "knock-in" mice model Human MH susceptibility.
A 1.1. To create a "hot-spot" region 2 MH 'knock in' mouse line (RyR1 G2434R). In addition to our recently
created R163C (region 1) and T4826I (region 3) RyR1 MHS mice. A 1.2.To determine the relationship between
the clinical MH phenotype and myoplasmic resting free calcium ([Ca2+],) in vivo, with contracture properties
in vitro for each heterozygous MH/CCD mouse. A1.3 To determine the relationship between IVCT and
myoplasmic resting [Ca2+] in myotubes from human biopsy samples. A1.4 To determine if genetic
background can rescue the birth lethal phenotype seen in homozygous MH/CCD mice. A1.5 To determine if
genetic background will lower or raise [Ca2+]i or sensitivity to halothane in heterozygous MH/CCD mice.
HYPOTHESIS II: Mutations responsible for human MH/CCD increase passive RyR1 "leak" and alter
the dynamics of EC coupling by enhancing ECCE and SOCE.
A 2.1 To analyze heterozygous and homozygous MH/CCD myotubes for abnormalities in EC coupling and
two forms of Ca2+ entry, ECCE and SOCE. A 2.2 To establish how halothane and dantrolene enhance and
diminish aberrant Ca2+ signaling in MH/CCD myotubes. A 2.3 To validate murine MH/CCD myotube model
results with myotubes obtained from humans with an analogous mutation.
Hypothesis III: The "Funnel" approach can be used to create a non-invasive screening test for
MH that has both a high degree of specificity and a high degree of sensitivity.
A 3.1. We will analyze whole blood transcriptional profiles from patients with known MHS RyR1 mutations
and use the Funnel approach to select a set of predictive markers to be used for future MHS screening.
项目1的长期目标是确定兰尼定受体(RyR1)的作用机制
肌病、恶性高热和中枢性核心病(MH/CCD)。我们的近期目标是
在小鼠身上建立合适的人类疾病模型,并用它们来研究RyR1的突变是如何改变的
细胞内钙稳态,并建立一种非侵入性诊断试验,具有高度
特异性和敏感性。
假设一:杂合子MH“敲入”小鼠模型人类MH易感性。
A 1.1。创建一个热点区域2 MH‘敲入’小鼠品系(RyR1 G2434R)。除了我们最近
建立了R163C(区域1)和T4826I(区域3)RyR1MHS小鼠。A1.2确定以下各项之间的关系
肌萎缩侧索硬化症的临床表型和肌浆内静息游离钙([Ca~(2+)]_2)
对每只杂合子MH/CD小鼠进行体外实验。A1.3确定IVCT和
肌浆静息[Ca~(2+)]在人体活检标本的肌管中。A1.4以确定基因是否
背景可以挽救在纯合子MH/CD小鼠中看到的出生致命表型。A1.5以确定是否
遗传背景会降低或提高杂合子MH/CD小鼠的[Ca~(2+)]i或对氟烷的敏感性。
假说二:导致人类MH/CD基因突变增加被动RyR1“泄漏”和改变
通过加强幼儿保育和社会经济发展而实现的欧共体耦合的动力学。
A 2.1分析杂合子和纯合子的MH/CCD肌管在EC偶联和
钙离子进入的两种形式,ECCE和SOCE。A 2.2确定氟烷和丹曲林如何增强和
减少MH/CCD型肌管中异常的钙信号。A 2.3验证小鼠MH/CD肌管模型
从具有类似突变的人身上获得的肌管的结果。
假设III:“漏斗”方法可用于创建一种非侵入性筛查试验
MH既有高度的特异性,又有高度的敏感性。
A 3.1。我们将分析已知MHS RyR1突变患者的全血转录图谱
并使用漏斗方法选择一组预测性标记用于未来的MHS筛查。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Paul D Allen其他文献
Adenoidectomy may decrease the need for a third set of tympanostomy tubes in children.
腺样体切除术可能会减少儿童对第三组鼓室造口管的需求。
- DOI:
- 发表时间:
2022 - 期刊:
- 影响因子:1.5
- 作者:
Sarah Hancock;Paul D Allen;Angel’Niqua Dixon;J. Faria;N. Vandjelovic;Margo McKenna Benoit - 通讯作者:
Margo McKenna Benoit
Polysomnogram outcomes in patients with laryngomalacia and obstructive sleep apnoea treated surgically versus non-surgically
手术治疗与非手术治疗的喉软化症和阻塞性睡眠呼吸暂停患者的多导睡眠图结果
- DOI:
10.1017/s0022215123000932 - 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Nicolas J. Casellas;Shalini Shah;S. Ravikumar;N. Vandjelovic;J. Faria;Paul D Allen;Margo McKenna Benoit - 通讯作者:
Margo McKenna Benoit
Drug-induced sleep endoscopy findings in surgically-naïve obese vs non-obese children.
药物诱导的睡眠内窥镜检查在未接受过手术的肥胖儿童与非肥胖儿童中的发现。
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:1.5
- 作者:
S. Lookabaugh;Margo K McKenna;S. Karelsky;M. Davis;Amanda Didas;Paul D Allen;J. Faria - 通讯作者:
J. Faria
Paul D Allen的其他文献
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{{ truncateString('Paul D Allen', 18)}}的其他基金
Mechanisms controlling Ca2+ dyshomeostasis in MH susceptible mice
MH 易感小鼠 Ca2 稳态失衡的控制机制
- 批准号:
9480595 - 财政年份:2016
- 资助金额:
$ 21.91万 - 项目类别:
Mechanisms controlling Ca2+ dyshomeostasis in MH susceptible mice
MH 易感小鼠 Ca2 稳态失衡的控制机制
- 批准号:
10016079 - 财政年份:2016
- 资助金额:
$ 21.91万 - 项目类别:
Muscle: Excitation/Contraction Coupling Gordon Research Conference
肌肉:兴奋/收缩耦合戈登研究会议
- 批准号:
8254759 - 财政年份:2011
- 资助金额:
$ 21.91万 - 项目类别:
Integral membrane protein overexpression using organ bioreactors
使用器官生物反应器过度表达整合膜蛋白
- 批准号:
7313034 - 财政年份:2007
- 资助金额:
$ 21.91万 - 项目类别:
Integral membrane protein overexpression using organ bioreactors
使用器官生物反应器过度表达整合膜蛋白
- 批准号:
7493750 - 财政年份:2007
- 资助金额:
$ 21.91万 - 项目类别:
Integral membrane protein overexpression using organ bioreactors
使用器官生物反应器过度表达整合膜蛋白
- 批准号:
7658832 - 财政年份:2007
- 资助金额:
$ 21.91万 - 项目类别:
Uncovering the Molecular Basis of Malignant Hyperthermia
揭示恶性高热的分子基础
- 批准号:
7223472 - 财政年份:2006
- 资助金额:
$ 21.91万 - 项目类别:
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