Targeted Improvement in Stem Cell Therapy for Leukemia and Bone Marrow Failure Sy

白血病和骨髓衰竭系统干细胞治疗的针对性改进

基本信息

批准号：
8597277
负责人：
QISHEN PANG
金额：
$ 30.8万
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：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8597277
关键词：
Acute Myelocytic Leukemia Adhesions Biological Assay Blood Bone Marrow Bone Marrow Transplantation CD34 gene Cell Adhesion Cell Count Cell Polarity Cells Clinical Cyclophosphamide Data Defect Disease Disease model Engraftment Environment Fanconi&apos s Anemia Genetic Goals Grant Healthcare Hematological Disease Hematopoietic Hematopoietic Stem Cell Mobilization Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Homing Human Hypersensitivity Image Inflammatory Inherited Knock-out Knowledge Lead Life Link Mediating Modeling Mus Pancytopenia Patients Population Property Regimen Research Design Second Primary Cancers Signal Transduction Stem cell transplant Stem cells Syndrome Therapeutic Tissues Toxic effect Transplantation conditioning congenic fludarabine gene correction gene therapy graft vs host disease high risk improved in vivo Model inhibitor/antagonist innovation irradiation leukemia leukemic stem cell migration mouse model mutant novel pre-clinical preconditioning primitive cell progenitor public health relevance residence rho GTP-Binding Proteins stem stem cell niche stem cell therapy success two-photon

项目摘要

DESCRIPTION (provided by applicant): Fanconi anemia (FA) is a major inherited bone marrow (BM) failure syndrome with extremely high risk of developing acute myeloid leukemia (AML). The only curable treatment for this devastating disease is stem cell and gene therapies through BM transplantation. We recently described cell-autonomous defects of FA hematopoietic stem cells (HSCs) in BM homing and engraftment, and showed that these impaired functions were associated with a decrease in the activity of the Rho GTPase Cdc42 known to be essential for cell polarity, adhesion and migration. These results provide the first evidence for a missing link between FA deficiency and inefficient HSC engraftment. More recently, our preliminary studies show that genetic deletion of Cdc42 in mice causes massive mobilization of HSCs from BM niche. Furthermore, we have developed CASIN, a Cdc42 activity-specific inhibitor, which can specifically, transiently, and reversibly down regulate Cdc42 and Cdc42-regulated signaling activities, allowing successful engraftment of CD34+ human blood progenitors as well as transplanted congenic murine HSCs without myeloablative or irradiation preconditioning. Using a FA knockout (Fanca) mouse model we have shown that preconditioning of Fanca-/- mice with CASIN allows significant engraftment of WT or FANCA gene-corrected Fanca-/- HSCs in the absence of myeloablative or irradiation conditioning. These preliminary data suggest that Cdc42 controls HSC residence in the BM niche through regulating cell adhesion. We hypothesize that cell-autonomous defect of FA HSC engraftment is a direct consequence of decreased Cdc42 activity, a property that could be utilized to vacant BM niche otherwise occupied by mutant HSC or leukemic stem cells (LSCs) and allow wild-type or gene-corrected HSC to engraft. The goals of the project are to study the mechanism of Cdc42 targeting in the context of HSC mobilization and BM niche engraftment, and ultimately to develop a novel preclinical regimen by targeting Cdc42 to improve stem cell and gene therapies for leukemia and BM failure diseases, clinical settings in which intensive preconditioning and scarce stem cell numbers critically limit success. The project presents the first mechanistic study aimed at targeting a critical HSC-niche interaction regulator in a significant health-care setting. The knowledge gained from the proposed study will not only improve mechanistic understanding of stem cell mobilization and engraftment in the context of stem cell transplantation, but also lead to a new avenue of research designed to target Cdc42 for developing innovative therapeutic regimens for stem cell and gene therapies in leukemia and BM failure diseases.

描述（申请人提供）：范可尼贫血（FA）是一种主要的遗传性骨髓（BM）衰竭综合征，具有极高的患急性髓性白血病（AML）的风险。对于这种毁灭性的疾病，唯一可治愈的治疗方法是通过骨髓移植进行干细胞和基因治疗。我们最近描述了 FA 造血干细胞 (HSC) 在 BM 归巢和植入过程中的细胞自主缺陷，并表明这些功能受损与 Rho GTPase Cdc42 活性降低相关，已知 Rho GTPase Cdc42 对细胞极性、粘附和移植至关重要。迁移。这些结果为 FA 缺乏和 HSC 植入效率低下之间缺失的联系提供了第一个证据。最近，我们的初步研究表明，小鼠中 Cdc42 的基因缺失会导致 BM 生态位中的 HSC 大量动员。此外，我们还开发了CASIN，一种Cdc42活性特异性抑制剂，它可以特异性地、短暂地、可逆地下调Cdc42和Cdc42调节的信号传导活性，从而允许CD34+人类血液祖细胞以及移植的同源小鼠HSC成功植入，而无需清髓或辐照预处理。使用 FA 敲除 (Fanca) 小鼠模型，我们发现用 CASIN 对 Fanca-/- 小鼠进行预处理，可以在没有清髓或照射条件的情况下显着植入 WT 或 FANCA 基因校正的 Fanca-/- HSC。这些初步数据表明，Cdc42 通过调节细胞粘附来控制 HSC 在 BM 生态位中的停留。我们假设 FA HSC 植入的细胞自主缺陷是 Cdc42 活性降低的直接结果，这种特性可用于腾出原本由突变 HSC 或白血病干细胞 (LSC) 占据的 BM 生态位，并允许野生型或基因-纠正 HSC 移植。该项目的目标是研究 HSC 动员和 BM 生态位植入背景下 Cdc42 靶向机制，并最终通过靶向 Cdc42 开发一种新型临床前治疗方案，以改善白血病和 BM 衰竭疾病的干细胞和基因治疗、临床密集的预处理和稀缺的干细胞数量严重限制了成功。该项目提出了第一项机制研究，旨在针对重要医疗保健环境中关键的 HSC 利基相互作用调节因子。从拟议的研究中获得的知识不仅将提高对干细胞移植背景下干细胞动员和植入的机制的理解，而且还开辟了一条新的研究途径，旨在针对 Cdc42 开发干细胞和基因的创新治疗方案白血病和骨髓衰竭疾病的治疗。