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：
10628000
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/10628000
关键词：
27-hydroxycholesterol ATP-Binding Cassette Transporters Acute Myelocytic Leukemia Adherence Adult Apoptosis Automobile Driving Award Biological Assay Blood Blood Vessels Bone Marrow Bone Marrow Purging Bone marrow failure Cell Cycle Cell Line Cell physiology Cells Cessation of life Cholesterol Cholesterol Homeostasis Circulation Coculture Techniques Complement Confocal Microscopy Cytochrome P450 Data Derivation procedure 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 Knowledge acquisition 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 Proliferating Reporter Research Reverse Transcriptase Polymerase Chain Reaction Role Source Spleen Splenectomy Stress Stromal Cell-Derived Factor 1 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.

项目摘要 /摘要人类急性髓样白血病（AML）是一种侵略性血液癌，死亡率高且差生存结果。大多数AML患者死于骨髓引起的并发症失败导致血液形成细胞的产生减少。但是，我们缺乏基本有关推动这种现象的机制的知识。基于最新数据，该数据显示造血茎和祖细胞几乎完全消耗在AML扩张期间，即使疾病负担低，也发生的人类AML异种移植物也发生拟议的工作将定义AML细胞扩展是否会置换正常的茎和祖细胞骨髓环境进入外围循环（AIM 1），使它们陷入脾脏内皮和血管周期生态位。该项目还旨在表征脾内皮和血管周围的生态位，其细胞分类学和能力的定义较差提供关键的利基因素（AIM 2）。这些研究将通过研究独特的研究来补充氧化酚，27-羟基胆固醇，由AML细胞在正常造血的失调中产生以旁分泌的方式（目标3）。这项工作将在遗传专家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细胞的表征和治疗靶向。我的共同导师欧文·韦斯曼（Irving Weissman）博士和纳库奇（Hiro Nakauchi）博士都以其知识而闻名骨髓和祖细胞细胞表征的专业知识脾。这项工作将在斯坦福大学医学院进行，这是世界一流的研究机构。拟议工作的结果有可能翻译现有，无毒和FDA 在疾病人群中，批准药物进入早期临床试验，这些试验很难治疗。如果资助后，该奖项将使我能够制定正常和恶性的严格培训计划造血，使我能够跨学科扩大研究，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 AML失败。