Animal Modeling and Clinical Resources Core

动物建模和临床资源核心

• 批准号: 9335297
• 负责人: David F Claxton
• 金额: $ 34.03万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335297
• 关键词: Acute Myelocytic Leukemia; Aliquot; Alpha Cell; Animal Model; Animals; Area; Biological; Biological Assay; Biological Models; Biology; Blood; Bone Marrow Cells; Cell Line; Cell model; Cells; Characteristics; Classification; Clinical; Clinical Data; Clonal Evolution; Cytogenetics; Data; Development; Disease; Disease remission; Engraftment; Exhibits; Fusion Oncogene Proteins; Genotype; Goals; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Human; In Vitro; Institutes; Laboratories; MLL-AF9; Malignant Neoplasms; Marrow; Materials Testing; Metabolism; Mixed-Lineage Leukemia; Modeling; Molecular; Morphology; Mus; Oncogenic; Outcome; Patients; Plasma; Preparation; Property; Proteins; Reagent; Research Personnel; Resources; Retroviridae; Role; Sampling; Sphingolipids; Stem cells; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Toxic effect; Treatment outcome; Umbilical Cord Blood; Validation; Xenograft Model; Xenograft procedure; base; cell bank; design; efficacy testing; humanized mouse; in vivo; in vivo Model; leukemia; leukemia treatment; leukemic stem cell; leukemogenesis; metabolomics; molecular subtypes; mouse model; next generation; novel; novel therapeutics; patient population; personalized medicine; progenitor; programs; repository; retransplantation; retroviral transduction; self-renewal; therapeutic evaluation; therapeutic target; therapy development

Human acute myelogenous leukemia (AML) is highly heterogeneous and, as demonstrated by this group, exhibits significant variability in sphingoiipid metabolism. Current therapy of AML is highly toxic, yielding ultimately inadequate outcomes for the vast majority of patients. Cell lines are limited in their representation of primary AML subtypes and manifest clonal evolution in culture, suggesting limitations in their relationship to the primary case material. The systematic study of these diseases thus requires access to primary samples representing a substantial pool of cases, and correlation of these samples to clinical data including treatment outcomes. Animal models of various kinds are available, but models representing direct leukemogenesis via expression of relevant oncogenic proteins and immunodeficient xenografts propagating primary AML, provide relevant platforms for studying developing therapies. In this Core, materials and models will be provided to each Project to allow completion of proposed objectives. The following specific aims will be pursued: Specific Aim 1: Expand and maintain the PSHCI leukemia cell bank to provide programmatic access to cell and plasma samples from a broad variety of AML patients and normal hematopoietic controls. Samples will be cryopreserved in multiple aliquots to allow repeated interrogation via developing technologies. Clinical data will be collected and available to provide biologically meaningful categorization of AMLs. Specific Aim 2: Develop and maintain a menu of animal models in which to test promising program-derived therapies. Two such models are available. Subaim 2A: Xenograft models of primary human leukemia have been developed in N0D/SCID/IL2ry (NSG) murine hosts and used as platforms for testing novel therapies. Multiple lines (originating from multiple AMLs of differing subtypes) will be passaged in NSG animals to provide in vivo validation of therapeutics. Human cord blood will be expanded in NSG mice to provide normal controls for in vivo toxicity studies. Subaim 2B: Murine syngeneic models of AML using retroviral transduction of murine bone marrow cells with fusion protein oncogenes. We have established a MLL-AF9 retroviral transduction model, which develops a stem cell derived leukemia shown to be inhibited by Project-derived therapeutics. This Core is essential to the overall Program, each project of which uses primary, cells and in vivo models as provided here. These materials and testing platforms will allow development of novel therapies for these lethal diseases.

人类急性髓细胞性白血病（AML）是高度异质性的，正如该组所证明的， 在鞘脂代谢中表现出显著的可变性。目前的AML治疗是高毒性的， 对绝大多数患者来说，最终的结果是不充分的。细胞系的代表性有限 原发性AML亚型和文化中表现出的克隆进化，表明它们之间的关系存在局限性 与主要案件的材料吻合因此，对这些疾病的系统研究需要获得初级保健服务。 代表大量病例的样本，以及这些样本与临床数据的相关性，包括 治疗结果。各种动物模型都是可用的，但代表直接免疫的模型。 通过相关致癌蛋白表达和免疫缺陷异种移植物增殖的白血病发生 原发性AML，为研究开发治疗提供相关平台。在这个核心中，材料和 将为每个项目提供模型，以完成拟议目标。以下具体 具体目标1：扩大和维持PSHCI白血病细胞库， 可编程访问来自各种AML患者和正常人的细胞和血浆样本 造血控制样本将以多个等分试样冷冻保存，以允许重复询问 通过发展技术。将收集临床数据，以提供生物学意义 AML的分类。具体目标2：开发和维护一份用于测试的动物模型菜单 有前途的程序衍生疗法有两种这样的模式。Subaim 2A： 已经在N 0 D/SCID/IL 2 ry（NSG）鼠宿主中开发了原发性人白血病， 用于测试新疗法的平台。多个细胞系（源自不同亚型的多个AML）将 在NSG动物中传代以提供治疗剂的体内验证。人类脐带血将是 在NSG小鼠中扩增以提供用于体内毒性研究的正常对照。Subaim 2B：小鼠同源 使用融合蛋白癌基因逆转录病毒转导鼠骨髓细胞的AML模型。我们 已经建立了MLL-AF 9逆转录病毒转导模型，该模型开发了干细胞衍生的白血病， 被项目衍生疗法抑制。这一核心对整个计划至关重要， 该项目使用本文提供的原代细胞和体内模型。这些材料和测试 平台将允许开发针对这些致命疾病的新疗法。