Modeling myelodysplasia

骨髓增生异常模型

基本信息

批准号：
10157422
负责人：
H. LEIGHTON GRIMES
金额：
$ 61.42万
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/10157422
关键词：
Affect Aging Allogenic Antibody Repertoire Azacitidine Biological Biopsy Cancer Model Cancer Survivor Categories Cell surface Cells Clonality Clone Cells DNA Sequence Alteration DNA sequencing Data Data Set Decitabine Dendritic Cells Development Diagnosis Diagnostic Disadvantaged Disease 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 Link 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 Reproducibility Research Resistance Risk Sampling Stem cell transplant Technology Therapeutic Therapeutic Agents Time Transitional Cell Work Xenograft Model Xenograft procedure aging population cell type comparative conditioning curative treatments cytokine epigenome high risk human data humanized mouse irradiation macrophage 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 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.

项目摘要骨髓增生综合征（MDS）是造血干细胞（HSC）的癌症人口和癌症幸存者。 MDS的唯一治疗方法是同种异体干细胞移植大多数MDS患者的局限性明显。结果，护理标准专注于低甲基化剂（HMA）偶氮丁胺（AZA）和剪替滨（DAC），它们总是会导致抗性和疾病进展。需要新的治疗学；但是，没有强大的模型 MDS加速临床前测试。我们已经产生了一个突破性的人性化异种移植物。消除调理并促进主要MD的小鼠模型。我们将验证诊断MDS患者材料的单细胞遗传和基因组表征模型并植入人源性小鼠中的相同细胞，显然使 Xenografting。接下来，我们将在鼠标模型中建立AZA的药效动力学端点并应用 AZA的经验剂量对模型的剂量。人类MDS材料将被捕获用于单个单元分析患者和异种移植物的-Aza后治疗。多态比较分析将敏锐地确定MISTRG-W41在MDS临床前测试中的实用性，通过说明在多大程度上异种移植物中类似地改变了患者AZA影响的计划。这种深层分子，基因型和对HMA对MDS的亚克隆和分层细胞组成的影响的表型理解将构建比较新颖靶向的治疗剂作为替代品，并发或后HMA的基础治疗方法。