Modeling myelodysplasia

骨髓增生异常模型

基本信息

批准号：
10541117
负责人：
H. LEIGHTON GRIMES
金额：
$ 57.71万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10541117
关键词：
Acceleration Affect Aging Allogenic Antibodies Azacitidine Biological Biopsy Cancer Model Cancer Survivor Categories Cell surface Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clonality DNA Sequence Alteration DNA sequencing Data Data Set Decitabine Dendritic Cells Development Diagnosis Diagnostic Disadvantaged Disease Progression Dose Dysmyelopoietic Syndromes Engraftment Epigenetic Process Erythroid Frequencies Future Genetic Genetic Transcription Genetically Engineered Mouse Genomics Genotype Hematologic Neoplasms Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Histologic Human Incidence Individual Interleukin-15 Knock-in Libraries Link Macrophage Macrophage Colony-Stimulating Factor Marrow Measures Modeling Modification Molecular Mus Mutation Osteoclasts Patients Pharmacodynamics Phenotype Physiological Population Preclinical Testing Production Proto-Oncogene Protein c-kit Publishing Reproducibility Research Resistance Risk Sampling Stem cell transplant Technology Therapeutic Therapeutic Agents Transitional Cell Work Xenograft Model Xenograft procedure aging population cell type comparative conditioning curative treatments cytokine epigenome high risk human data humanized mouse improved irradiation leukemia monocyte mouse model multiple omics mutant new therapeutic target novel therapeutics pre-clinical programs repaired response single cell analysis single cell technology standard of care stem stem cells targeted treatment transcriptome treatment response

项目摘要

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.

项目概要骨髓增生异常综合征 (MDS) 是一种造血干细胞 (HSC) 癌症，随着年龄的增长而增加人口和癌症幸存者。骨髓增生异常综合征唯一的治疗方法是同种异体干细胞移植在大多数 MDS 患者中存在明显的局限性。因此，护理标准的重点是去甲基化剂 (HMA) 氮胞苷 (AZA) 和地西他滨 (DAC)，它们总是会导致耐药性和疾病进展。迫切需要新的治疗方法；然而，目前还没有稳健的模型 MDS 加速临床前测试。我们已经产生了突破性的人源化异种移植受体小鼠模型消除了调节并促进原发性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和基因组特征建立模型以及移植到人源化小鼠中的相同细胞，清楚地描绘了转录影响异种移植。接下来，我们将在小鼠模型中建立 AZA 的药效学终点并应用根据经验得出的 AZA 模型剂量。人类MDS材料将被捕获用于单细胞分析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 MDS 临床前测试的程度，深入确定 MSTRG-W41 的效用受 AZA 影响的患者程序在异种移植中也发生了类似的变化。这种深层的分子、基因型和将建立对 HMA 对 MDS 亚克隆和分层细胞组成影响的表型理解比较新型靶向治疗药物作为替代方案、同时或 HMA 后的基础治疗方法。