Modulating endothelial-specific signaling to enhance functional hematopoiesis.

调节内皮特异性信号传导以增强功能性造血功能。

• 批准号: 9149403
• 负责人: Jason Mathew Butler
• 金额: $ 41.94万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9149403
• 关键词: Adult; Affect; Apoptotic; Back; Blood; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Cell Cycle; Cell Maintenance; Cell physiology; Cells; Clinical; Clinical Trials; Coculture Techniques; DNA; DNA Damage; Data; Data Set; Development; Dose; Endothelial Cells; Endothelium; Equilibrium; Foundations; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Immune system; In Vitro; Injury; Laboratories; Lead; Lethal Dose 50; Life; Maintenance; Metabolic; Modeling; Morbidity - disease rate; Mus; Myelosuppression; NF-kappa B; NFKB Signaling Pathway; Natural regeneration; Organ Culture Techniques; Outcome; Oxidative Phosphorylation; Pancytopenia; Pathway interactions; Play; Production; Protocols documentation; Radiation; Recovery; Regimen; Research Project Grants; Research Proposals; Role; Signal Pathway; Signal Transduction; Stem cell transplant; Stem cells; System; Techniques; Testing; Therapeutic; Transgenic Mice; Transplantation; Vascular System; anaerobic glycolysis; base; design; fitness; in vivo; injured; insight; irradiation; loss of function; metabolic profile; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; paracrine; pre-clinical; promoter; regenerative; repaired; research study; self-renewal; stem cell niche; transcriptome sequencing

Adult hematopoietic stem cells (HSCs) are defined by their ability to undergo self-renewal and maintain the capacity to generate all types of mature hematopoietic cells within the blood and immune system. The bone marrow (BM) microenvironment supplies critical pro-hematopoietic signals that regulate the maintenance of the hematopoietic system. Understanding these signals may lead to the development of novel strategies to increase the number of HSCs that would be available in a clinical setting to treat a wide variety of hematological diseases. The overall goal of this research project is to define mechanisms by which NF-kB signaling in the BM vascular niche regulates the maintenance of the HSC pool during homeostatic and regenerative conditions. We have recently demonstrated that endothelial cells (ECs) play an essential role in maintaining HSC homeostasis through activation of the Akt pathway, enabling ECs to maintain and expand functional HSCs. However, the signaling pathways downstream of Akt responsible for endowing ECs with the instructional capacity to regulate the self-renewal and differentiation of HSCs are unknown. We have found that the inhibiting NF-kB signaling in Akt-activated ECs results in robust expansion of functional mouse HSCs thereby enhancing hematopoietic recovery following myelosuppression, in part, by protecting the BM microenvironment. Based on these observations, we hypothesize that the inhibition of NF-kB signaling pathway in BMECs regulates the maintenance of the HSC pool by protecting the hematopoietic and vascular system from radiation-induced DNA and metabolic damage. To study the role of NF-kB signaling in BMECs, we will use a transgenic mouse model in which NF-kB signaling is inhibited under the control of a vascular specific promoter. Utilizing novel techniques developed in our laboratory that enable us to isolate and cultivate ECs from the BM, we will be able to test if inhibiting the Akt/NF-kB signaling axis within the vascular niche 1) protects the HSC from radiation induced DNA and cellular damage, 2) helps maintain and restore the proper metabolic profile during hematopoietic regeneration, 3) rejuvenates the BM vascular niche and hematopoietic system by transplanting properly activated BMECs, and 4) enhances the expression of novel pro-hematopoietic factors that promote homeostatic and regenerative hematopoiesis. These studies will begin to unravel the mechanisms by which ECs support the balance between HSC self-renewal and differentiation. These studies will lay the foundation to develop new therapeutic strategies aimed at rejuvenating the HSC niche and restoring the hematopoietic compartment following myeloablative treatments.

成体造血干细胞 (HSC) 的定义是它们具有自我更新和 维持在血液和免疫中产生各种类型成熟造血细胞的能力 系统。骨髓（BM）微环境提供关键的促造血信号来调节 造血系统的维护。了解这些信号可能会导致发展 增加 HSC 数量的新策略可用于临床治疗 多种血液系统疾病。该研究项目的总体目标是通过以下方式定义机制： BM 血管生态位中的 NF-kB 信号传导调节 HSC 池的维持 稳态和再生条件。我们最近证明内皮细胞（EC）发挥着 通过激活 Akt 通路，在维持 HSC 稳态中发挥重要作用，使 EC 能够 维持和扩展功能性 HSC。然而，Akt 下游的信号通路负责 赋予 ECs 调节 HSCs 自我更新和分化的指导能力 未知。我们发现，抑制 Akt 激活的 EC 中的 NF-kB 信号传导会导致强大的 功能性小鼠 HSC 的扩增，从而增强造血恢复 骨髓抑制，部分是通过保护骨髓微环境来实现的。根据这些观察，我们 假设 BMEC 中 NF-kB 信号通路的抑制可调节 通过保护造血和血管系统免受辐射诱导的 DNA 影响来保护 HSC 库， 代谢损伤。为了研究 NF-kB 信号在 BMEC 中的作用，我们将使用转基因小鼠模型 其中 NF-kB 信号传导在血管特异性启动子的控制下受到抑制。利用小说 我们实验室开发的技术使我们能够从 BM 中分离和培养 EC，我们将 能够测试抑制血管生态位内的 Akt/NF-kB 信号轴 1) 是否可以保护 HSC 辐射引起的 DNA 和细胞损伤，2) 有助于维持和恢复适当的代谢状况 在造血再生过程中，3) 通过以下方式使 BM 血管生态位和造血系统恢复活力 移植适当激活的 BMEC，4) 增强新型促造血因子的表达 促进体内平衡和再生性造血。这些研究将开始揭开 ECs 支持 HSC 自我更新和分化之间平衡的机制。这些 研究将为开发新的治疗策略奠定基础，旨在振兴 HSC 生态位 并在清髓治疗后恢复造血室。