Targeting Cdc42 for bone marrow transplant therapies

靶向 Cdc42 进行骨髓移植治疗

• 批准号: 9269547
• 负责人: YI ZHENG
• 金额: $ 35.69万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269547
• 关键词: Actins; Adhesions; Adverse effects; Affect; Affinity; Animals; Autologous Stem Cell Transplantation; Binding; Blood; Blood donor; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; CD34 gene; Cell Count; Cell Maintenance; Cell Survival; Cell Therapy; Cells; Chimerism; Clinic; Clinical; Complex; Congenic Mice; Crystallization; Cytoskeleton; Data; Defect; Disease; Dysmyelopoietic Syndromes; Engraftment; Family; Fibronectins; Future; Gene Targeting; Generations; Genetic; Goals; Guanine Nucleotides; Guanosine Triphosphate Phosphohydrolases; Harvest; Hematologic Neoplasms; Hematological Disease; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homing; Human; Hypersensitivity; Immunodeficient Mouse; In Vitro; Individual; Integrins; Kinetics; Knock-out; Lead; Malignant Neoplasms; Mediating; Methods; Modeling; Morbidity - disease rate; Multiple Myeloma; Mus; Nodal; Pancytopenia; Patients; Pharmaceutical Chemistry; Pharmacology; Play; Property; Reaction; Regimen; Residencies; Roentgen Rays; Role; Safety; Signal Transduction; Specificity; Stem cell transplant; Stem cells; Structural Models; Structure; Structure-Activity Relationship; Study models; Syndrome; Testing; Therapeutic; Toxic effect; Transplantation; Umbilical Cord Blood; Validation; Work; analog; base; biochemical model; bone marrow failure syndrome; chemokine; clinical application; clinical practice; conditioning; curative treatments; cytotoxicity; design; drug discovery; efficacy testing; gene therapy; improved; inhibitor/antagonist; irradiation; leukemia; migration; mortality; mouse model; novel; novel therapeutics; pre-clinical; preconditioning; progenitor; public health relevance; residence; rho; rho GTP-Binding Proteins; small molecule; small molecule inhibitor; standard of care; stem cell therapy; success

 DESCRIPTION (provided by applicant): Transplantation of mobilized hematopoietic stem cells (HSCs) has become a standard of care for hematologic malignancies and blood diseases such as leukemia, bone marrow failure syndromes, and multiple myeloma. Novel methods promoting HSC engraftment are needed to improve the efficacy and safety of stem cell and gene therapies, especially for those patients where conventional HSC mobilization regimens are not effective or myeloablative conditioning leads to morbidity and mortality. To this end, developing more effective approaches for HSC mobilization and allowing increased engraftment and stable chimerism of quantity-limited CD34+ human HSCs or gene therapy-corrected HSCs could significantly impact on future stem cell transplantation practice for hematologic malignancies. The Rho family GTPase Cdc42 plays critical roles in regulating cytoskeleton dynamics, ß1 integrin-mediated adhesion, and SDF-1a induced directional migration, functions that are essential for HSC residence in the bone marrow niche. In preliminary studies we have characterized a conditional gene targeted mouse model and identified a Cdc42 specific small molecule inhibitor to define the role of Cdc42 in HSC residency in the bone marrow. We show that gene targeting or pharmacological targeting of Cdc42 causes massive mobilization of functional HSCs, transient opening of bone marrow niche, and effective engraftment of syngeneic or autolagous transplanted HSCs. Our results suggest that Cdc42 constitutes a critical nodal of intracellular signal flows involved in HSC maintenance in the bone marrow, and lead to our central hypothesis that Cdc42 is essential for HSC residence in the BM niche and represents a useful target for HSC engraftment, properties useful for improving bone marrow transplant efficacy. The aims of the proposed studies are (1) to define the mechanism of action of lead Cdc42 inhibitor and improve the lead efficacy by medicinal chemistry, and (2) to establish a proof of principle of Cdc42 targeting as a non- myeloablative conditioning regimen for HSC engraftment in mouse models. By achieving the goals of these early stage drug discovery studies, we may establish a new method for blood stem cell transplantation that may significantly impact on future cell therapies for blood malignancies.

 描述（由申请人提供）：动员造血干细胞（HSC）移植已成为恶性血液病和血液疾病（如白血病、骨髓衰竭综合征和多发性骨髓瘤）的标准治疗。需要促进HSC植入的新方法来提高干细胞和基因疗法的功效和安全性，特别是对于常规HSC动员方案无效或清髓性预处理导致发病率和死亡率的那些患者。为此，开发更有效的HSC动员方法，并允许数量有限的CD34+人HSC或基因治疗校正的HSC的植入和稳定嵌合体的增加，可能会显著影响未来恶性血液病的干细胞移植实践。Rho家族GTdCdc42在调节细胞骨架动力学、β 1整联蛋白介导的粘附和SDF-1 α诱导的定向迁移中起关键作用，这些功能对于HSC在骨髓小生境中的驻留是必需的。在初步研究中，我们已经表征了条件基因靶向小鼠模型，并鉴定了Cdc42特异性小分子抑制剂，以确定Cdc42在骨髓中HSC驻留中的作用。我们发现，Cdc42的基因靶向或药理学靶向导致功能性HSC的大规模动员，骨髓小生境的短暂开放，以及同基因或自体移植的HSC的有效植入。我们的研究结果表明，Cdc42构成了一个关键节点的细胞内信号流参与造血干细胞在骨髓中的维护，并导致我们的中心假设，Cdc42是必不可少的造血干细胞居住在BM龛，并代表了一个有用的目标，造血干细胞移植，性能有用的改善骨髓移植的疗效。拟定研究的目的是：（1）确定Cdc42先导化合物抑制剂的作用机制，并通过药物化学提高其疗效;（2）在小鼠模型中建立Cdc42靶向作为HSC植入的非清髓性预处理方案的原理证明。通过实现这些早期药物发现研究的目标，我们可能会建立一种新的血液干细胞移植方法，这可能会对未来血液恶性肿瘤的细胞疗法产生重大影响。