Functional Role of Tetraspanin CD82 in Hematopoietic Stem Cell Interactions

四跨膜蛋白 CD82 在造血干细胞相互作用中的功能作用

• 批准号: 10452239
• 负责人: Jennifer Gillette
• 金额: $ 37.62万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452239
• 关键词: Adhesions; Attenuated; Biochemistry; Bone Marrow; Cadherins; Cell Communication; Cell Cycle; Cells; Complement Factor B; Complex; Coupled; Data; Development; Family; Foundations; Growth Factor Receptors; Hand; Health; Hematology; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hemorrhage; Human; Image; Imaging Techniques; Individual; Infection; Injury; Integrins; KAI1 gene; Knock-out; Knockout Mice; Knowledge; Ligands; Light; Link; Mediating; Membrane; Molecular; Mutation Analysis; Myelosuppressive Therapy; Natural regeneration; Patient-Focused Outcomes; Phenotype; Publishing; Radiation exposure; Receptor Signaling; Recovery; Regenerative capacity; Regenerative response; Regulation; Research; Role; Scaffolding Protein; Signal Transduction; Stress; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Work; base; cell regeneration; combinatorial; exhaustion; genetic manipulation; hematopoietic stem cell quiescence; imaging approach; improved; innovation; insight; mouse model; mutant; neutralizing antibody; novel; prevent; protein protein interaction; recruit; response; scaffold; single molecule; spatiotemporal; therapeutic target; trafficking; transplantation therapy

PROJECT SUMMARY The significant cellular demand of the hematopoietic system is maintained by a rare pool of tissue-specific, hematopoietic stem and progenitor cells (HSPCs) that are primarily found in a quiescent state. Upon hematopoietic stresses, such as significant bleeding, overwhelming infection, radiation exposure and myelosuppressive therapy, HSPCs are rapidly recruited into cell cycle, but ultimately must return to quiescence. The ability to transiently modulate HSPC return to quiescence has the potential to extend the activation of HSPCs and significantly improve overall patient outcomes from hematopoietic stresses and for transplantation therapies. However, in order to leverage a transient extension of HSPC activation to improve the regenerative response to stress, we must first understand the mechanisms by which the complex network of cell-intrinsic and -extrinsic signaling within the bone marrow are coupled to regulate HSPC quiescence. The objective of our current proposal is to evaluate the tetraspanin membrane-scaffold protein, CD82, as a tractable target to modulate HSPC quiescence signaling within the bone marrow. Tetraspanins are a family of membrane-scaffold proteins with the unique ability to regulate cell-cell/cell-matrix interactions and modulate intracellular signaling, thus linking cell-microenvironment interactions to downstream signaling consequences. Our new preliminary data indicate that the CD82 scaffold promotes a quiescent HSPC phenotype when cells are niche engaged and implicate a role for Transforming Growth Factor  (TGF) signaling. Thus, in this proposal, we will test the hypothesis that the CD82 membrane scaffold promotes HSPC quiescence by organizing and enhancing the signaling activity of a TGF receptor complex within the bone marrow niche. In Specific Aim 1, we will determine the molecular mechanisms by which CD82 modulates the TGFβ signaling response of HSPCs. For Specific Aim 2, we will identify the mechanism by which CD82 promotes the spatial activation of TGF signaling locally within the bone marrow niche during hematopoietic stress. In Specific Aim 3, we will evaluate CD82 as a therapeutic target to improve the hematopoietic regeneration response to hematologic injury. In pursuit of these aims, we will apply an innovative combinatorial approach that includes mutational analysis, biochemistry and sophisticated imaging techniques, which will enable us to obtain a multi- scale understanding of the mechanisms by which CD82 regulates TGF signal transduction in the context of hematopoietic stress. Moreover, the successful completion of the proposed aims will be significant because we expect to integrate mechanistic insights across multiple scales to identify the multifaceted contribution of CD82 to the regulation of TGF signaling in the context of hematopoietic stress and quiescence, which will build a foundation for the development of improved therapeutics that locally target the complex TGF signaling cascade within the bone marrow.

项目摘要 造血系统的显著细胞需求由罕见的组织特异性， 造血干细胞和祖细胞（HSPC）主要以静止状态存在。后 造血压力，如严重出血，压倒性感染，辐射暴露和 在骨髓抑制疗法中，HSPC被迅速募集到细胞周期中，但最终必须返回到细胞周期中。 安静瞬时调节HSPC恢复到静止的能力具有延长HSPC的存活时间的潜力。 激活HSPC，并显著改善造血应激的总体患者结局， 移植疗法然而，为了利用HSPC激活的短暂延长来改善 再生反应的压力，我们必须首先了解的机制，复杂的网络 骨髓内的细胞内源性和外源性信号传导耦合以调节HSPC静止。的 我们目前的建议的目的是评估四跨膜蛋白膜支架蛋白，CD 82，作为 易处理的靶点来调节骨髓内的HSPC静止信号传导。四跨膜蛋白是一类 膜支架蛋白具有调节细胞-细胞/细胞-基质相互作用和调节 细胞内信号传导，从而将细胞-微环境相互作用与下游信号传导结果联系起来。 我们的新的初步数据表明，当细胞增殖时，CD 82支架促进静止的HSPC表型。 是小生境参与的，并暗示转化生长因子β（TGF β）信号传导的作用。所以针对本 根据该提案，我们将通过以下方式检验CD 82膜支架促进HSPC静止的假设： 组织和增强骨髓龛内TGF β受体复合物的信号传导活性。在 具体目标1，我们将确定CD 82调节TGFβ信号转导的分子机制， HSPC的响应。对于特异性目的2，我们将确定CD 82促进空间表达的机制。 在造血应激过程中，在骨髓小生境内局部激活TGF β 1信号传导。具体目标 3，我们将评估CD 82作为改善造血再生反应的治疗靶点， 血液损伤为了实现这些目标，我们将采用创新的组合方法，包括 突变分析，生物化学和先进的成像技术，这将使我们能够获得一个多- 规模的理解的机制，其中CD 82调节TGF β信号转导的背景下， 造血应激此外，成功实现拟议目标将具有重要意义，因为我们 我希望在多个尺度上整合机制性见解，以确定CD 82的多方面贡献 在造血应激和静止的背景下调节TGF β 1信号传导，这将建立一个 为开发局部靶向复杂TGF β 1信号传导的改良疗法奠定了基础 在骨髓中级联。