Canine Disease and Transplantation Model

犬疾病与移植模型

• 批准号: 10207256
• 负责人: Brian Joseph Hayes
• 金额: $ 3.43万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207256
• 关键词: Address; Alleles; Anemia; Animal Model; Animals; Area; Award; Biological; Biological Assay; Biological Models; Biological Products; Biology; Biomedical Research; Bone Marrow; Canis familiaris; Cell Maintenance; Cells; Chimerism; Cloning Vectors; Collection; Colony-Forming Units Assay; Complement; Complex; Coupled; DNA; Development; Disease model; Dog Diseases; Drug resistance; Dysmyelopoietic Syndromes; Engineering; Enzymes; Genetic Variation; Germ-Line Mutation; HLA Antigens; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hereditary Disease; Histocompatibility; Human; IL2RG gene; In Vitro; Infrastructure; Knowledge; Longevity; Longitudinal Studies; Measures; Medicine; Modeling; Modernization; Modification; Mus; Mutation; Names; Non-Malignant; Play; Procedures; Process; Production; Pyruvate Kinase; Quality Control; RNA; Reagent; Recording of previous events; Research; Research Personnel; Resources; Role; Services; Severe Combined Immunodeficiency; Site; Somatic Mutation; Stem cell transplant; System; Technology; Therapeutic Studies; Time; Tissues; Translating; Transplantation; Work; Xenograft procedure; animal care; base; biological effect of radiation; comparative; conditioning; cost; experience; experimental study; expression vector; gene therapy; human leukocyte antigen testing; in vivo; in vivo Model; leukocyte antigen typing; next generation sequencing; novel; peripheral blood; pre-clinical; preclinical study; quality assurance; reconstitution; response; sperm cell; stem cell biology; stem cell function; stem cells; tissue repair; tool; transplant model; vector

PROJECT SUMMARY/ABSTRACT - Canine Disease and Transplantation Model (Canine) Core Hematopoiesis is a complex process which is regulated by many internal and external factors. Numerous variables synergize or antagonize to influence differentiation and stem cell maintenance. These mechanisms that control the hematopoietic system are difficult to deconstruct into fundamental parts. Thus, hematopoietic stem cells are difficult to maintain in vitro, because the cells' responses to culture conditions are dictated by so many influences. The conclusions drawn from in vitro cell-based assays are then necessarily limited by the complexity of the system. There are many meritorious reasons to manipulate stem cells: correct a mutation, render them drug resistance, and control their antigenic profile to name a few. They can be modified for several purposes, but critically they must retain stem cell function. The only definitive assay for stem cell function is hematopoietic reconstitution following lethal conditioning. Therefore, animal model systems are used to reveal the fundamental biology of hematopoietic stem cells. However, no single animal model can fully recapitulate the human hematopoietic system, so we propose to offer the canine as a model to complement hematopoietic studies in mice. Canines address some of the key differences between mice and humans notably size, lifespan, and genetic diversity. Additionally, dogs have relatively large litters, which can be useful for histocompatibility and transplantation. This Canine Core will use engineered somatic mutations, spontaneous germline mutations, and develop canine biological reagents for non-malignant hematopoietic research. The accumulated knowledge of canine husbandry and stem cell transplantation, as well as existing facilities at Fred Hutch, make this Canine Core unique. In conjunction with the expertise of the other CCEH Cores, the entire breadth of an experiment can be completed. The Cell P&P core can isolate and store stem cells, these cells can be modified in the Tools core, the stem cell character can be verified in a canine-to- mouse transplant in the Xenografting Core, and the Canine Core can provide a large animal in vivo model to study the biology of stem cell modifications. Internal and external users of this core will be able to take advantage of decades of experience enriching stem cells, manipulating them, and assaying them in xenografts, as well as the 60 years of institutional experience with the canine model.

项目摘要/摘要 - 犬疾病和移植模型（犬）核心 造血是一个复杂的过程，受到许多内部和外部因素的调节。很多的 变量协同或拮抗影响分化和干细胞维持。这些机制 控制造血系统的部分很难分解为基本部分。因此，造血 干细胞很难在体外维持，因为细胞对培养条件的反应取决于以下因素： 许多影响。从体外基于细胞的测定中得出的结论必然受到以下因素的限制： 系统的复杂性。操纵干细胞有许多优点：纠正突变， 使它们产生耐药性，并控制它们的抗原特征等等。它们可以修改为 有几个目的，但最重要的是它们必须保留干细胞功能。干细胞唯一确定的检测方法 功能是致死调节后的造血重建。因此，动物模型系统 用于揭示造血干细胞的基本生物学。然而，没有任何一种动物模型能够完全 概括了人类造血系统，因此我们建议提供犬科动物作为模型来补充 小鼠造血研究。犬科动物解决了小鼠和人类之间的一些关键差异 尤其是体型、寿命和遗传多样性。此外，狗的窝数相对较多，这可能很有用 用于组织相容性和移植。这个犬类核心将使用工程体细胞突变， 自发种系突变，并开发用于非恶性造血的犬生物试剂 研究。犬类饲养和干细胞移植方面积累的知识以及现有的 Fred Hutch 的设施使这个 Canine Core 独一无二。结合其他 CCEH 的专业知识 核心，可以完成整个实验。 Cell P&P 核心可以分离和储存干细胞 细胞，这些细胞可以在工具核心中进行修改，干细胞特征可以在犬类到- 异种移植核心中的小鼠移植物和犬科核心可以提供大型动物体内模型 研究干细胞修饰的生物学。该核心的内部和外部用户将能够使用 凭借数十年富集、操作和分析干细胞的经验 异种移植，以及 60 年的犬类模型机构经验。