MitoCluster: an integrated phenotyping and mouse model generation platform for mitochondrial disease and dysfunction.

MitoCluster：用于线粒体疾病和功能障碍的集成表型分析和小鼠模型生成平台。

• 批准号: MC_PC_21046
• 负责人: Robert Pitceathly
• 金额: $ 382.69万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MC_PC_21046
• 关键词: MitoCluster; integrated; phenotyping; mouse; model

Mitochondria are tiny energy generators that exist in large numbers (100s-1000s) inside human cells. Primary mitochondrial diseases (PMDs) are a large group of genetic disorders that impair mitochondria and the body's ability to make energy. They can cause disabling symptoms that may impact very severely on quality of life. Though individually rare, as a group PMDs are a common cause of nervous system diseases. Inherited disorders are caused by alterations in our genetic code (DNA) that carries the instructions for making proteins, the building blocks of life. PMDs are caused by alterations in DNA inside the cell nucleus or a small amount of DNA (mtDNA) inside the mitochondria themselves. PMDs can cause symptoms at birth, in childhood or during adulthood, and cause a wide variety of medical problems, depending on the body parts most severely affected. As mitochondria are present in almost all cells, any system in the body can be affected and patients can develop deafness, blindness, heart problems, seizures, diabetes and gut problems among others. Muscles are particularly susceptible to reduced energy, which causes fatigue and weakness. Unfortunately, there are currently no effective treatments for PMDs. Importantly, the effects of faulty mitochondria seen in PMDs are also present in other common diseases (genetic and non-genetic), such as dementia, diabetes and cancer. Consequently, a better understanding of PMDs could also help us to understand these more common conditions. A barrier to PMD research, and other diseases in which mitochondria play a role, is a lack of relevant mouse models. Consequently, developing good mouse models is a major goal of the mitochondrial research community. Recreating PMDs in mice will allow researchers to confirm that genetic mutations cause PMD symptoms, find new ways to measure the disease over time and develop and test new treatments that can then more safely progress to trials in humans. It has been very challenging to create mtDNA models of human PMDs in mice (as it is difficult to alter the small amounts of DNA that sit inside mitochondria). However, new tools to change mtDNA have recently been established. Also, modern techniques to measure mouse development, movement and behaviour that can be applied over long periods without stressing mice will allow researchers to study PMDs in these animals more accurately and humanely.MitoCluster is a network of researchers based in the UK and Italy who will develop new mouse models of PMDs and apply advanced techniques to evaluate these and existing mouse models, to: (1) deliver new insights, therapies and biological indicators (biomarkers) of PMDs; and (2) help understand the role of mitochondria in other common diseases (e.g., dementia, diabetes and cancer). Our team combines doctors and scientists who have expert knowledge of mitochondrial function and genetics, PMDs and clinical trials. We will work closely with drug companies with strong interest in developing therapies for PMDs and help prioritise the treatments most likely to benefit patients by studying them in mice first, and link closely with researchers of other disorders linked with faulty mitochondria, to ensure the knowledge we generate advances understanding in these diseases. Finally, we will meet regularly with patients and carers affected by PMDs and advocacy groups, to ensure we address questions that are important to the wider PMD community.Our group is committed to "3Rs" principles for animal research. We will reduce the number of mice used by using all data/samples collected for multiple tests, by sharing findings with other researchers and by replacing mice with cell lines or flies for early research. We will refine current methods to measure mitochondria in mice to make them less stressful, more accurate and reproducible, and more relevant to humans.

线粒体是微小的能量发生器，大量存在于人类细胞内（100 - 1000）。原发性线粒体疾病（PMD）是一大组损害线粒体和身体制造能量的能力的遗传性疾病。它们可能导致致残症状，可能严重影响生活质量。虽然个别罕见，但作为一个群体，PMD是神经系统疾病的常见原因。遗传性疾病是由我们的遗传密码（DNA）的改变引起的，遗传密码（DNA）携带着制造蛋白质（生命的基石）的指令。PMD是由细胞核内的DNA或线粒体本身内的少量DNA（mtDNA）的改变引起的。PMD可在出生时、儿童期或成年期引起症状，并根据受影响最严重的身体部位引起各种各样的医疗问题。由于线粒体存在于几乎所有细胞中，因此体内的任何系统都可能受到影响，患者可能会出现耳聋，失明，心脏问题，癫痫发作，糖尿病和肠道问题等。肌肉特别容易受到能量减少的影响，这会导致疲劳和虚弱。不幸的是，目前还没有有效的治疗PMD的方法。重要的是，PMD中出现的缺陷线粒体的影响也存在于其他常见疾病（遗传和非遗传）中，如痴呆症，糖尿病和癌症。因此，更好地了解PMD也可以帮助我们了解这些更常见的情况。PMD研究以及线粒体在其中发挥作用的其他疾病的障碍是缺乏相关的小鼠模型。因此，开发良好的小鼠模型是线粒体研究界的主要目标。在小鼠中重建PMD将使研究人员能够确认基因突变导致PMD症状，找到新的方法来测量疾病的时间，并开发和测试新的治疗方法，然后可以更安全地进行人体试验。在小鼠中创建人类PMD的mtDNA模型非常具有挑战性（因为很难改变线粒体内的少量DNA）。然而，最近已经建立了改变mtDNA的新工具。此外，测量小鼠发育、运动和行为的现代技术可以长期应用，而不会对小鼠造成压力，这将使研究人员能够更准确和人性化地研究这些动物的PMD。MitoCluster是一个由英国和意大利的研究人员组成的网络，他们将开发新的PMD小鼠模型，并应用先进的技术来评估这些小鼠模型和现有的小鼠模型，以：（1）提供PMD的新见解、疗法和生物学指标（生物标志物）;以及（2）帮助理解线粒体在其他常见疾病中的作用（例如，痴呆、糖尿病和癌症）。我们的团队结合了具有线粒体功能和遗传学，PMD和临床试验专业知识的医生和科学家。我们将与对开发PMD疗法有浓厚兴趣的制药公司密切合作，并通过首先在小鼠中研究患者来帮助优先考虑最有可能使患者受益的治疗方法，并与与线粒体缺陷相关的其他疾病的研究人员密切联系，以确保我们产生的知识能够促进对这些疾病的理解。最后，我们将定期与受PMD影响的患者和护理人员以及倡导团体会面，以确保我们解决对更广泛的PMD社区至关重要的问题。我们的团队致力于动物研究的“3R”原则。我们将通过使用为多项测试收集的所有数据/样本，与其他研究人员分享研究结果，以及在早期研究中用细胞系或苍蝇取代小鼠来减少使用小鼠的数量。我们将改进目前测量小鼠线粒体的方法，使其压力更小，更准确和可重复，并且与人类更相关。

项目成果

Factors associated with the severity of COVID-19 outcomes in people with neuromuscular diseases: Data from the International Neuromuscular COVID-19 Registry.

• DOI: 10.1111/ene.15613
• 发表时间: 2023-02
• 期刊: EUROPEAN JOURNAL OF NEUROLOGY
• 影响因子: 5.1
• 作者: Pizzamiglio, Chiara;Pitceathly, Robert D. S.;Lunn, Michael P.;Brady, Stefen;De Marchi, Fabiola;Galan, Lucia;Heckmann, Jeannine M.;Horga, Alejandro;Molnar, Maria J.;Oliveira, Acary S. B.;Pinto, Wladimir B. V. R.;Primiano, Guido;Santos, Ernestina;Schoser, Benedikt;Servidei, Serenella;Souza, Paulo V. Sgobbi;Venugopalan, Vishnu;Hanna, Michael G.;Dimachkie, Mazen M.;Machado, Pedro M.
• 通讯作者: Machado, Pedro M.

Manipulation of Murine Mitochondrial DNA Heteroplasmy with mtZFNs.

用 mtZFN 操纵鼠线粒体 DNA 异质性。

• DOI: 10.1007/978-1-0716-2922-2_23
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Nash PA

Development of a diagnostic framework for vestibular causes of dizziness and unsteadiness in patients with multisensory neurological disease: a Delphi consensus.

多感觉神经系统疾病患者头晕和不稳定的前庭原因诊断框架的开发：德尔菲共识。

• DOI: 10.1007/s00415-023-11640-2
• 发表时间: 2023
• 期刊: Journal of neurology
• 影响因子: 6
• 作者: Male AJ

mitoTALEN reduces the mutant mtDNA load in neurons

• DOI: 10.1016/j.omtn.2024.102132
• 发表时间: 2024-02-16
• 期刊: MOLECULAR THERAPY NUCLEIC ACIDS
• 作者: Bacman，Sandra R.;Barrera-Paez，Jose Domingo;Moraes，Carlos T.
• 通讯作者: Moraes，Carlos T.

Advances in methods to analyse cardiolipin and their clinical applications.

• DOI: 10.1016/j.trac.2022.116808
• 发表时间: 2022-12
• 期刊: Trends in analytical chemistry : TRAC
• 作者: Bautista JS;Falabella M;Flannery PJ;Hanna MG;Heales SJR;Pope SAS;Pitceathly RDS
• 通讯作者: Pitceathly RDS