Dissecting the Mechanism of Acute Myeloid Leukemia Induced Bone Marrow Failure to Identify Therapeutic Interventions

剖析急性髓系白血病导致骨髓无法识别治疗干预措施的机制

基本信息

批准号：
10403496
负责人：
TIAN YI ZHANG
金额：
$ 16.36万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10403496
关键词：
27-hydroxycholesterol ATP-Binding Cassette Transporters Acute Myelocytic Leukemia Adherence Adult Apoptosis Archives Automobile Driving Award Biological Assay Blood Blood Circulation Bone Marrow Bone Marrow Purging Bone marrow failure CXCL12 gene Cell Cycle Cell Line Cell physiology Cells Cessation of life Cholesterol Cholesterol Homeostasis Coculture Techniques Complement Confocal Microscopy Cytochrome P450 Data Discipline Disease Elements Endothelium Environment Enzyme-Linked Immunosorbent Assay Enzymes Extramedullary Hematopoiesis FDA approved Failure Flow Cytometry Frequencies Funding Genetic Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Human Hydroxycholesterols Immunofluorescence Immunologic In Vitro Institution Knowledge Laboratories Learning Lipoprotein Receptor Liver Luciferases Malignant - descriptor Malignant Neoplasms Marrow Mentors Mentorship Metabolic Pathway Mus Nature Operative Surgical Procedures Pathology Pathway interactions Patients Peripheral Pharmaceutical Preparations Population Pregnancy Process Production Reporter Research Reverse Transcriptase Polymerase Chain Reaction Role Source Spleen Splenectomy Stress Taxonomy Techniques Testing Therapeutic Intervention Training Transcript Translating Universities Western Blotting Work Xenograft Model Xenograft procedure acute myeloid leukemia cell burden of illness cytopenia early phase clinical trial human disease in vivo insight medical schools mesenchymal stromal cell monocyte mortality novel paracrine peripheral blood pre-clinical progenitor protein expression single-cell RNA sequencing skills stem stem cells survival outcome therapeutic target transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY / ABSTRACT Human acute myeloid leukemia (AML) is an aggressive blood cancer with a high mortality rate and poor survival outcomes. The majority of AML patients die from complications arising from bone marrow failure which causes decreased production of blood forming cells. However, we lack fundamental knowledge regarding the mechanism driving this phenomenon. Building upon recent data which shows near complete depletion of hematopoietic stem and progenitors during AML expansion in human AML xenografts which occurred even with low level of disease burden, the proposed work will define whether AML cell expansion displaces normal stem and progenitors from the bone marrow environment into peripheral circulation (Aim 1) whereby they become entrapped in the splenic endothelial and perivascular niche. This project also aims to characterize the splenic endothelial and perivascular niche which remains poorly defined with respect to its cellular taxonomy and ability to provide critical niche factors (Aim 2). These studies will be complemented by investigating the unique oxysterol, 27-hydroxycholesterol, produced by AML cells in the dysregulation of normal hematopoiesis in a paracrine manner (Aim 3). This work will be performed under the primary mentorship of Dr. Ravi Majeti, an expert in the genetic characterization and therapeutic targeting of AML cells using primary human AML xenografts. My co- mentors, Dr. Irving Weissman and Dr. Hiro Nakauchi, are both renowned for their knowledge and expertise in the characterization of hematopoietic stem and progenitors cells in the bone marrow and spleen. This work will be conducted at Stanford University School of Medicine, a world-class research institution. The results of the proposed work have the potential to translate existing, non-toxic and FDA approved drugs into early phase clinical trials in a disease population that is very difficult to treat. If funded, this award will allow me to pursue a rigorous training plan in normal and malignant hematopoiesis, enabling me to expand my research across disciplines, learn new techniques, and acquire the knowledge and skills to establish an independent laboratory focused on the reversal of bone marrow failure in AML.

项目概要/摘要人类急性髓系白血病（AML）是一种侵袭性血癌，死亡率高，且预后较差。生存结果。大多数 AML 患者死于骨髓并发症导致造血细胞生成减少的失败。然而我们缺乏根本有关驱动这种现象的机制的知识。根据最近的数据显示造血干细胞和祖细胞几乎完全耗尽在人类 AML 异种移植物中的 AML 扩增过程中，即使疾病负担水平较低，也会发生这种情况，拟议的工作将确定 AML 细胞扩增是否会取代正常的干细胞和祖细胞骨髓环境进入外周循环（目标 1），由此它们被困在脾内皮和血管周围微环境。该项目还旨在表征脾内皮细胞和血管周围生态位，其细胞分类和能力仍然不明确提供关键的利基因素（目标 2）。这些研究将通过调查独特的氧甾醇，27-羟基胆固醇，由 AML 细胞在正常造血功能失调时产生以旁分泌方式（目标 3）。这项工作将在遗传学专家 Ravi Majeti 博士的主要指导下进行。使用原代人 AML 异种移植物对 AML 细胞进行表征和治疗靶向。我的同事导师 Irving Weissman 博士和 Hiro Nakauchi 博士均以其知识和经验而闻名骨髓中造血干细胞和祖细胞特征的专业知识脾。这项工作将在世界一流的研究机构斯坦福大学医学院进行机构。拟议工作的结果有可能转化现有的、无毒的和 FDA 批准药物进入很难治疗的疾病人群的早期临床试验。如果资助后，这个奖项将使我能够在正常和恶性的情况下实行严格的培训计划造血功能，使我能够跨学科扩展我的研究，学习新技术并获得建立专注于骨髓逆转的独立实验室的知识和技能反洗钱失败。