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 造血系统的显着细胞需求由罕见的组织特异性池维持 造血干细胞和祖细胞（HSPC）主要在静止状态下。之上 造血应激，例如明显的出血，压倒性感染，辐射暴露和 骨髓抑制疗法，HSPC迅速招募到细胞周期，但最终必须恢复 静止。瞬时调节HSPC返回静止的能力具有扩展的潜力 HSPC的激活，并显着改善造血应激的总体患者预后 移植疗法。但是，为了利用HSPC激活的瞬态扩展以改进 对压力的再生反应，我们必须首先了解复杂网络的机制 骨髓内的细胞中性和 - 超支信号传导耦合以调节HSPC静止。这 我们当前建议的目的是评估四叠素膜膜蛋白CD82作为A 可调节骨髓内HSPC静止信号传导的可牵引目标。四翼胺是一个家庭 具有独特的调节细胞/细胞 - 矩阵相互作用并调节的独特能力的膜型蛋白质 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后果联系起来。 我们的新初步数据表明，当细胞时，CD82支架会促进静止的HSPC表型 利基市场是否参与并暗示了转化生长因子（TGF）信号传导的作用。那，这是 提案，我们将检验以下假设：CD82膜支架通过 组织和增强骨髓生态位TGF受体复合物的信号传导活性。在 特定目标1，我们将确定CD82调节TGFβ信号传导的分子机制 HSPC的响应。对于特定目标2，我们将确定CD82促进空间的机制 在造血应激期间，骨髓小裂局部局部TGF信号的激活。在特定目标中 3，我们将评估CD82作为改善造血再生反应的治疗靶标 血液损伤。为了追求这些目标，我们将采用一种创新的组合方法，包括 突变分析，生物化学和复杂的成像技术，这将使我们能够获得多个 对CD82调节TGF信号传输的机制的规模了解 造血压力。此外，提议的目标的成功完成将是重要的，因为我们 期望整合多个尺度的机械见解，以确定CD82的多方面贡献 在造血压力和静止的背景下，TGF信号传导的调节，这将建立一个 开发改进的治疗基础，该治疗局部针对复杂的TGF信号传导 骨髓内的级联反应。