Expanding the Utility of Severe Combined Immuno-Deficient (SCID) Pig Models

扩大严重联合免疫缺陷 (SCID) 猪模型的用途

• 批准号: 9060414
• 负责人: Christopher Tuggle
• 金额: $ 65.88万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060414
• 关键词: Address; Age-Months; Alleles; Allogenic; Amino Acid Sequence; Animal Model; Animals; Area; B-Lymphocytes; Biology; Bone Marrow; Bone Marrow Transplantation; Bone Regeneration; Cancer cell line; Cardiac; Cell Therapy; Cells; Clinic; Counseling; Development; Engraftment; Family suidae; Gene Mutation; Generations; Genes; Genetic; Genetic Code; Goals; Heart Research; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heterozygote; Human; Human Biology; Immune; Immune system; Immunophenotyping; Inbreeding; Institutes; Knowledge; Letters; Life; Maintenance; Mesenchymal Stem Cells; Modeling; Mus; Mutate; Mutation; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Killer Cells; Neonatal; Outcome; Outcomes Research; Patients; Peptide Sequence Determination; Phenotype; Physiology; Population Genetics; Pre-Clinical Model; Preclinical Testing; Preparation; Procedures; Proteins; Protocols documentation; Regenerative Medicine; Research; Research Personnel; Research Project Grants; Residual state; Resources; Safety; Scientist; Splice-Site Mutation; Stem Cell Research; Stem cells; Study models; T-Lymphocyte; Terminator Codon; Testing; Therapeutic; Translating; Translations; Transplantation; United States National Institutes of Health; Variant; Work; Wound Healing; Xenograft procedure; adaptive immunity; artemis; base; biocontainment facility; cartilage regeneration; cohort; comparative; design; gene product; genetic resource; graft vs host disease; human stem cells; improved; in vivo Model; innovation; interest; leukemia/lymphoma; mouse model; mutant; novel; null mutation; pathogen; pre-clinical; pre-clinical research; public health relevance; stem cell therapy; translational medicine; vaccine evaluation

DESCRIPTION (provided by applicant): The promise of stem cell-based therapies is currently not being fully realized due to the lack of appropriate pre-clinical animal models. Consequently, there remains a critical need to develop better animal models that better translate results from preclinical research trials to the patient. Scientific advancements addressing this problem have been realized through the identification of a naturally occurring Severe Combined Immuno- Deficient (SCID) line of pigs. The SCID pig model has been preliminarily characterized as both T and B lymphocytes deficient and thus is deficient in adaptive immunity. The pig is known to be an excellent model for human biology due to similarities in size, physiology and genetic code; and this novel SCID model has been successfully engrafted with multiple human cancer cell lines, indicating high potential as an in vivo model for many areas of regenerative medicine testing. We have received multiple requests and interest in obtaining this model. The research areas of these interested scientists spans many areas of regenerative medicine research, from cardiac progenitor cell therapies to cartilage regeneration studies, to the use of mesenchymal stem cells for bone regeneration and wound repair, to improving treatment of graft versus host disease in hematopoietic stem cell (HSC) transplants. A pig SCID model will have a specific positive impact in that it will provide researchers with alternative and comparative models for such stem cell research. Our long-term goal is to create validated SCID models for broad use in preclinical testing of such stem cell based therapies. The specific objectives of this application are to further develop this model for regenerative medicine testing, as well as improve its ability to engraft human cells into the bone marrow so that a human immune system can develop. Such an advanced model could be broadly used for vaccine testing and the study of human-specific pathogens. To maximize the broad use of these models, we will further develop protocols and design and test biocontainment facilities for practical utilization of our current pi lines. Our rationale for the proposed research is that the SCID pig is physiologically and phylogenetically more similar to humans than the mouse and therefore may more accurately reflect how proposed stem cells will survive and function in humans. This project is innovative because a SCID pig model has not been fully developed, and development of such model may result in significantly and rapidly advancing the fundamental knowledge of SCID into translational medicine capable of accelerating regenerative medicine research. With regard to expected outcomes, the successful completion of this project will create multiple genetic resources and associated animal procedures that will be highly desirable for SCID based modeling for research projects focused on the efficacy of stem cell therapeutics. Thus these unique resources are expected to have a significant impact in accelerating the translation of regenerative medicine research into the clinic.

描述(申请人提供)：由于缺乏合适的临床前动物模型，干细胞疗法的前景目前还没有完全实现。因此，仍然迫切需要开发更好的动物模型，以便更好地将临床前研究试验的结果转化为患者。通过鉴定一种自然产生的严重联合免疫缺陷(SCID)猪品系，已经实现了解决这一问题的科学进步。SCID猪模型的初步特征是T、B淋巴细胞均缺乏，存在适应性免疫缺陷。由于猪在大小、生理和遗传密码方面的相似之处，它被认为是一个很好的人类生物学模型；这个新的SCID模型已经成功地移植到多个人类癌细胞系中，这表明在许多再生医学测试领域中具有很高的体内模型的潜力。我们已经收到了多个请求，并有兴趣获得此模型。这些感兴趣的科学家的研究领域横跨再生医学研究的许多领域，从心脏前体细胞疗法到软骨再生研究，到使用间充质干细胞进行骨再生和伤口修复，再到改善造血干细胞(HSC)移植中移植物抗宿主病的治疗。猪的SCID模型将产生特定的积极影响，因为它将为研究人员提供此类干细胞研究的替代和比较模型。我们的长期目标是创建经过验证的SCID模型，以广泛用于此类基于干细胞的疗法的临床前测试。该应用程序的具体目标是进一步开发用于再生医学测试的模型，以及提高其能力 将人体细胞移植到骨髓中，以便人类免疫系统能够发育。这种先进的模型可以广泛用于疫苗测试和人类特有病原体的研究。为了最大限度地广泛使用这些模型，我们将进一步开发协议，设计和测试生物遏制设施，以便实际使用我们目前的pi系列。我们建议进行这项研究的理由是，与老鼠相比，SCID猪在生理和系统发育上与人类更相似，因此可能更准确地反映建议的干细胞如何在人类体内存活和发挥作用。这个项目之所以具有创新性，是因为SCID猪模型还没有完全开发出来，而这种模型的发展可能会使SCID的基础知识显著和迅速地发展到能够加速再生医学研究的转化医学中。关于预期结果，该项目的成功完成将创造多种遗传资源和相关的动物程序，这将是基于SCID的建模非常可取的，用于侧重于干细胞疗法疗效的研究项目。因此，这些独特的资源有望对加速将再生医学研究转化为临床产生重大影响。