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Modeling myelodysplasia

Modeling myelodysplasia
骨髓增生异常模型
批准号:
10157422
负责人:
H. LEIGHTON GRIMES
金额:
$61.42万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-01-01 至 2025-12-31

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中文摘要
翻译
项目摘要 骨髓增生异常综合征(MDS)是一种造血干细胞(HSC)恶性肿瘤,随着年龄的增长,其发病率呈上升趋势 人口和癌症幸存者。MDS的唯一治愈性治疗是异基因干细胞移植 在大多数MDS患者中具有显著的局限性。因此,标准治疗侧重于 低甲基化剂(HMA)、氮杂胞苷(AZA)和地西他滨(DAC),它们总是导致耐药性 和疾病进展。迫切需要新的治疗方法;然而,没有强有力的模型, MDS加速临床前测试。我们创造了一种突破性的人源化异种移植受体 小鼠模型,其消除了预处理并促进了原发性MDS的植入。我们将验证 通过治疗前诊断性MDS患者材料的单细胞遗传学和基因组表征的模型 和移植到人源化小鼠中的相同细胞,清楚地说明了 异种移植接下来,我们将在小鼠模型中建立AZA的药效学终点,并应用 AZA的药物衍生剂量。将采集人MDS材料用于单细胞 分析来自患者和异种移植物的AZA治疗后。多组学比较分析将 通过说明MISTRG-W 41在MDS临床前试验中的应用程度, AZA受影响的程序在异种移植中也发生了类似的变化。这种深层的分子、基因型和 HMA对MDS亚克隆和分级细胞组成的影响的表型理解将建立 比较新型靶向治疗药物作为替代药物、同时使用或HMA后使用的基础 治疗方法。
英文摘要
PROJECT SUMMARY Myelodysplastic Syndromes (MDS) are a cancer of the hematopoietic stem cell (HSC) on the rise in the aging population and cancer survivors. The only curative treatment for MDS is allogeneic stem cell transplantation with marked limitations in the majority of MDS patients. As a result, standard-of-care focuses on hypomethylating agents (HMA) azacytidine (AZA) and decitabine (DAC), which invariably result in resistance and disease progression. There is a dire need for new therapeutics; however, there are no robust models of MDS to accelerate preclinical testing. We have generated a breakthrough humanized xenograft-recipient mouse model which eliminates conditioning and facilitates engraftment of primary MDS. We will validate the model by single-cell genetic and genomic characterization of diagnostic MDS patient material before therapy and of the same cells engrafted in humanized mice, clearly dellineating the transcriptional impact of xenografting. Next, we will establish pharmacodynamic endpoints for AZA within the mouse model and apply the empirically-derived dose of AZA to the model. Human MDS material will be captured for single cell analyses post-AZA therapy from both patients and xenografts. The multi-omics comparative analyses will incisively determine the utility of MISTRG-W41 for MDS preclinical testing, by illustrating the extent to which AZA-affected programs in patients are similarly changed in the xenograft. This deep molecular, genotypic, and phenotypic understanding of HMA effects on subclonal and hierarchical cellular compositions of MDS will build the basis for comparison of novel-targeted-therapeutic agents as alternatives, concurrent, or post-HMA therapeutic approaches.
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Modeling myelodysplasia
  • 批准号:
    10320969
  • 项目类别:
  • 资助金额:
    $59.25万
  • 财政年份:
    2021
  • 负责人:
    H. LEIGHTON GRIMES
  • 依托单位:
Modeling myelodysplasia
  • 批准号:
    10541117
  • 项目类别:
  • 资助金额:
    $57.71万
  • 财政年份:
    2021
  • 负责人:
    H. LEIGHTON GRIMES
  • 依托单位:
A generalizable framework for linking single-cell genomic states with cell fate outcomes in hematopoiesis
  • 批准号:
    10410480
  • 项目类别:
  • 资助金额:
    $106.15万
  • 财政年份:
    2020
  • 负责人:
    H. LEIGHTON GRIMES
  • 依托单位:
A generalizable framework for linking single-cell genomic states with cell fate outcomes in hematopoiesis
  • 批准号:
    10237929
  • 项目类别:
  • 资助金额:
    $106.15万
  • 财政年份:
    2020
  • 负责人:
    H. LEIGHTON GRIMES
  • 依托单位:
海外基金