Development of a Porcine Model of Ataxia-Telangiectasia

共济失调毛细血管扩张猪模型的建立

• 批准号: 8496150
• 负责人: Christopher Rogers
• 金额: $ 60.82万
• 依托单位: EXEMPLAR GENETICS, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496150
• 关键词: ATM function; ATM gene; Affect; Anatomy; Animal Model; Animals; Ataxia Telangiectasia; Biochemical; Biological Assay; Brain; Brain Neoplasms; Breeding; Cells; Chromosomal Instability; Clinical; Complex; Defect; Development; Diabetes Mellitus; Disease; Early Onset Cerebellar Ataxia; Embryo; Exhibits; Failure; Family suidae; Female; Fibroblasts; Functional disorder; Gene Targeting; Generations; Genes; Genetic Engineering; Globulins; Goals; Growth; Heterozygote; Human; Immune system; Immunologic Deficiency Syndromes; Inborn Genetic Diseases; Individual; Industry; Injection of therapeutic agent; Insulin Resistance; Ionizing radiation; Malignant Neoplasms; Medical; Mission; Modeling; Molecular; Motor; Mus; Mutation; Names; Nature; Neurologic; Nuclear; Organ; Pathogenesis; Patients; Phase; Phenotype; Physical therapy; Physiological; Physiology; Predisposition; Pregnancy; Proteins; Research Personnel; Resources; Series; Source; Speech Therapy; Symptoms; Testing; Therapeutic; Thymus Gland; Xenograft procedure; ataxia telangiectasia mutated protein; base; fetal; human disease; improved; leukemia/lymphoma; male; mouse model; mutant; novel diagnostics; novel therapeutics; nuclear transfer; progenitor; public health relevance; somatic cell nuclear transfer; symptom management; tool

DESCRIPTION (provided by applicant): Ataxia-telangiectasia (A-T) is a multi-systemic, recessively inherited disorder that affects between 1 in 40,000 to 1 in 100,000 individuals worldwide. It is characterized primarily by early onset cerebellar ataxia and telangiectasia, from which the disease name is derived. In addition, patients also exhibit a number of other clinical symptoms including increased susceptibility to cancer (lymphomas, leukemia, brain tumors), immunodeficiency, insulin-resistant diabetes, chromosomal instability, sensitivity to ionizing radiation, susceptibility to bronchopulmonary disease, and the absence, or almost complete absence, of a thymus. Current treatments for A-T are directed toward the management of symptoms. Physical and speech therapy can improve the lives of patients, and ¿-globulin injections can be given to support the immune system. However, no treatment is directed at the underlying defect. Consequently, A-T remains a fatal disease. The development of improved therapies for A-T is currently limited by the lack of an animal model that fully, and accurately, recapitulates the multi-systemic nature of this disease. A number of mouse models of A-T have been developed over the years by the targeted disruption of the mouse Atm gene, and these models have proved invaluable for studying some aspects of ATM function and A-T disease. However, no single mouse model fully replicates the complex clinical symptoms observed in human disease, and more importantly, none of the murine models develop the severe neurological phenotype that is the hallmark of human A-T disease. The failure of mouse models to develop the classical symptoms of A-T is likely the result of physiological, anatomical, and developmental differences between the two species. In contrast, pigs may serve as a better model in which to study human disease given that their development, anatomy, and physiology are more closely related to that of humans. Given that the development and anatomy of the pig brain more closely resembles that of humans than mice, mutations in the porcine ATM gene may result in many of the same neurological changes that are observed in A-T patients. Therefore, the ultimate goal of this proposal is to develop and commercialize a porcine model of A-T by disrupting the ATM gene. We intend to accomplish this in two steps by combining gene-targeting and somatic cell nuclear transfer (SCNT). In this proposal, ATM+/- fetal fibroblasts that were developed in Phase I will be used as nuclear donors for somatic cell nuclear transfer. Nuclear transfer embryos will be transferred to recipient females for gestation. Resulting piglets will have one targeted ATM gene. We will breed heterozygotes to produce ATM-/- pigs and perform a thorough molecular, biochemical, and physiological characterization. Finally, we will establish long-term breeding herds. This project is intended to produce a porcine model of ataxia-telangiectasia that will provide academic and industry researchers with an opportunity to better understand the consequences of ATM dysfunction, the pathogenesis of A-T disease, and provide an improved model in which to develop and test new therapeutic strategies.

描述（由适用提供）：共济失调 - 塞氏菌（A-T）是一种多系统的，隐性遗传性的疾病，影响了全球40,000至100,000人中的100,000人。它的特征是早期发作小脑共济失调和telangiectia，从中得出了疾病名称。此外，患者还表现出许多其他临床症状，包括增加对癌症的易感性（淋巴瘤，白血病，脑肿瘤），免疫缺陷，胰岛素耐药性糖尿病，染色体不稳定性，对电离辐射的敏感性，对支气管疾病疾病的易感性以及几乎完全缺乏症状或几乎完全缺乏。 A-T的当前治疗方法用于治疗症状。物理和言语疗法可以改善患者的生活，并且可以进行`` - 全球蛋白注射剂来支持免疫系统。但是，没有治疗针对潜在的缺陷。因此，A-T仍然是致命疾病。目前，改进的A-T疗法的开发受到缺乏完全，准确地概括该疾病的多系统性质的动物模型的限制。多年来，由于小鼠ATM基因的靶向破坏，已经开发了许多A-T的小鼠模型，这些模型对于研究ATM功能和A-T疾病的某些方面而被证明是无价的。但是，没有一只小鼠模型完全复制在人类疾病中观察到的复杂临床症状，更重要的是，鼠模型均未形成严重的神经系统型，这是人类A-T疾病的标志。小鼠模型未能发展出A-T的经典症状的未能是两种物种之间物理，解剖和发育差异的结果。相比之下，鉴于猪的发育，解剖学和生理学与人类的发育，解剖学和生理学更紧密相关，可以作为研究人类疾病的更好模型。鉴于猪脑的发育和解剖学与人类的发育和解剖相比，猪ATM基因中的突变可能会导致许多相同的神经系统变化，而A-T患者观察到。因此，该提案的最终目标是通过破坏ATM基因来开发和商业化A-T的猪模型。我们打算通过将基因靶向和体细胞核转移（SCNT）结合到两个步骤来完成这一目标。在此提案中，ATM +/-胎儿成纤维细胞 我们将在第一阶段开发作为体细胞核转移的核供体。核转移胚胎将转移到受体女性中进行妊娠。由此产生的小猪将具有一个靶向的ATM基因。我们将繁殖杂合子产生ATM - / - 猪，并进行彻底的分子，生化和物理表征。最后，我们将建立长期的繁殖牛群。该项目旨在产生一种猪telaxiectictia的猪模型，该模型将为学术和行业研究人员提供更好地了解ATM功能障碍的后果，A-T疾病的发病机理的后果，并为开发和测试新的治疗策略提供了改进的模型。