Modulating signaling pathways in endothelial cells to abate leukemic progression

调节内皮细胞信号通路以减缓白血病进展

基本信息

批准号：
9893715
负责人：
Jason Mathew Butler
金额：
$ 40.51万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893715
关键词：
Abate Acute Myelocytic Leukemia Address Affect Age Aging Alleles Animal Model Arthritis Biological Assay Blood Vessels Bone Marrow Cardiovascular Diseases Cell Line Cell Separation Cell physiology Cells Chimeric Proteins Coculture Techniques Data Defect Development Disease Endothelial Cells Endothelium Equilibrium Exhibits Gene Expression Regulation Genetic Goals Growth Growth Factor Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic System Hematopoietic stem cells Impairment In Vitro In complete remission Inflammatory Instruction Intervention Knock-in Laboratories Lead Leukemic Cell MAPK Signaling Pathway Pathway MLL-AF9 Maintenance Malignant Neoplasms Modeling Morbidity - disease rate Mus Myelosuppression NF-kappa B NFKB Signaling Pathway Natural regeneration Non-Malignant Pathway interactions Patients Phenotype Physiological Predisposition Premature aging syndrome Production Protocols documentation Radiology Specialty Recovery Regimen Research Project Grants Research Proposals Residual Neoplasm Signal Pathway Signal Transduction Stress Supporting Cell System Testing Therapeutic Time Up-Regulation Vascular System acute myeloid leukemia cell age related aged base body system bone aging design experimental study functional decline hematopoietic stem cell differentiation hematopoietic stem cell expansion hematopoietic stem cell self-renewal in vitro Model in vivo innovation leukemia leukemia initiating cell mortality mouse model novel overexpression paracrine prevent public health relevance regenerative restoration success t(9 11)(p22 q23)treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this research project is to determine how physiological aging of the bone marrow (BM) vascular niche results in a dysregulation of signaling pathways which leads to the disruption of the cellular cross talk between the BM vascular niche and the hematopoietic stem cell (HSC). In this proposal, we aim to define the mechanisms by which age-related alterations to the BM vascular niche can enhance the progression of hematopoietic malignancies. We have demonstrated that Akt signaling in BM endothelial cells (BMECs) supports the maintenance of the HSCs, whereas age-related increases in Mapk and NF-kB signaling promote the differentiation of HSCs into lineage-committed progeny. Our preliminary data demonstrates that the overexpression of Mapk signaling specifically in ECs leads to premature aging (phenotypic and functional) of the HSC and that inhibiting NF-kB signaling in Akt-activated ECs results in a robust in vivo expansion of functional HSCs thereby enhancing hematopoietic recovery following myelosuppression. Additionally, we have found that Akt, Mapk, and NF-kB signaling are upregulated in in vivo BMECs when in contact with AML cells and that Akt-activation in ECs can expand phenotypic leukemia initiating cells leading to aggressive disease. Based on this evidence, we hypothesize that disruption of key signaling pathways in aged BMECs deprive the hematopoietic system from EC-derived instructive signals that are essential for the maintenance and regeneration of non-malignant hematopoietic cells. To formally address this hypothesis, our laboratory has devised novel in vivo and in vitro models that will allow us to determine if modulation of endothelial-specific signaling pathways can "safe guard" normal HSCs while increasing the susceptibility of the leukemic cells to chemotherapeutic regimens, effectively giving a competitive advantage to the non-malignant hematopoietic system. Utilizing our in vivo mouse models and ex vivo instructive mouse EC/HSC co-culture system that can be utilized to assess the growth potential and aggressiveness of leukemic cells grown on various BMEC lines, we will be able to test 1) if aged BMECs and aberrantly activated (Mapk) BMECs can support the outgrowth of aggressive leukemic clones, 2) if modulation of the Akt/NF-kB signaling axis can reverse age-related hematopoietic defects and give a competitive advantage to non-malignant hematopoietic cells at steady state and following chemotherapeutic intervention, and 3) whether the activation state of the BM endothelium drive the onset of AML using an in vivo genetic mouse model of AML. These studies will begin to unravel the mechanisms by which dysregulation of BMECs in an aged BM microenvironment can lose their instructive capacity to support the proper balance between HSC self-renewal and differentiation. The success of these studies may potentially open up new avenues for the development of a wide array of therapeutic strategies designed as an effective means to diminish leukemic burden and minimal residual disease by augmenting the sensitivity of leukemic cells to chemotherapeutic regimens.

描述（由申请人提供）：该研究项目的总体目标是确定骨髓 (BM) 血管生态位的生理老化如何导致信号通路失调，从而导致 BM 血管之间的细胞串扰中断在本提案中，我们的目标是确定与年龄相关的 BM 血管生态位改变可以促进造血系统恶性肿瘤进展的机制。 BM 内皮细胞 (BMEC) 中的 Akt 信号传导支持 HSC 的维持，而与年龄相关的 Mapk 和 NF-kB 信号传导促进 HSC 分化为谱系定向子代。我们的初步数据表明，Mapk 信号传导的过度表达特异性。 EC 中的 NF-kB 信号传导会导致 HSC 过早衰老（表型和功能），并且抑制 Akt 激活的 EC 中的 NF-kB 信号传导会导致体内功能的强劲扩展。 HSC 从而增强了骨髓抑制后的造血恢复。此外，我们发现，当与 AML 细胞接触时，体内 BMEC 中的 Akt、Mapk 和 NF-kB 信号传导上调，并且 EC 中的 Akt 激活可以扩大表型白血病起始细胞，从而导致表型白血病起始细胞的增殖。基于这一证据，我们认为老年 BMEC 关键信号通路的破坏会导致造血系统失去 EC 衍生的疾病。对于非恶性造血细胞的维持和再生至关重要的指导性信号为了正式解决这一假设，我们的实验室设计了新颖的体内和体外模型，使我们能够确定内皮特异性信号传导途径的调节是否可以“保护”正常造血干细胞，同时增加白血病细胞对化疗方案的敏感性，有效地为非恶性造血系统提供竞争优势。利用我们的体内小鼠模型和离体指导性小鼠 EC/HSC 共培养系统可用于评估在各种 BMEC 系上生长的白血病细胞的生长潜力和侵袭性，我们将能够测试 1) 是否老化 BMEC 和异常激活（ Mapk) BMEC 可以支持侵袭性白血病克隆的生长，2) 如果 Akt/NF-kB 信号轴的调节可以逆转与年龄相关的造血缺陷并给出稳态和化疗干预后非恶性造血细胞的竞争优势，以及 3) 使用 AML 体内遗传小鼠模型，BM 内皮细胞的激活状态是否会驱动 AML 的发生。老化的 BM 微环境中 BMEC 的失调可能会失去其支持 HSC 自我更新和分化之间适当平衡的指导能力。这些研究的成功可能会开辟新的领域。开发多种治疗策略的途径，旨在通过增强白血病细胞对化疗方案的敏感性来减少白血病负担和微小残留病的有效手段。