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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）：本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传导通路失调，从而导致BM血管生态位和造血干细胞（HSC）之间的细胞串扰中断。在这个建议中，我们的目标是确定机制，年龄相关的改变BM血管生态位可以促进造血系统恶性肿瘤的进展。我们已经证明，骨髓内皮细胞（BMEC）中的Akt信号支持HSC的维持，而Mapk和NF-kB信号的年龄相关性增加促进HSC分化为谱系定向子代。我们的初步数据表明，特异性地在EC中Mapk信号传导的过表达导致HSC的过早老化（表型和功能性），并且抑制Akt激活的EC中的NF-κ B信号传导导致功能性HSC的稳健的体内扩增，从而增强骨髓抑制后的造血恢复。此外，我们发现Akt、Mapk和NF-kB信号传导在体内BMEC中与AML细胞接触时上调，并且EC中的Akt活化可以扩增表型白血病起始细胞，导致侵袭性疾病。基于这一证据，我们假设，在老年BMEC中的关键信号通路的中断剥夺了造血系统从EC衍生的指导性信号，这是必不可少的非恶性造血细胞的维持和再生。为了正式解决这一假设，我们的实验室已经设计了新的体内和体外模型，这将使我们能够确定内皮特异性信号通路的调节是否可以“保护”正常HSC，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（其可用于评估在各种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）老化的BMEC和异常活化（Mapk）的BMEC是否可以支持侵袭性白血病克隆的生长，2）如果Akt/NF-kB信号传导轴的调节可以逆转年龄相关的造血缺陷并在稳态和化疗干预后给予非恶性造血细胞竞争优势，和3）使用AML的体内遗传小鼠模型，BM内皮的活化状态是否驱动AML的发作。这些研究将开始揭示老化BM微环境中BMEC失调可能失去其支持HSC自我更新和分化之间适当平衡的指导能力的机制。这些研究的成功可能会为开发一系列治疗策略开辟新的途径，这些治疗策略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最小残留疾病。