Functional Role of Tetraspanin CD82 in Hematopoietic Stem Cell Interaction

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: 9038432
• 负责人: Jennifer Gillette
• 金额: $ 37.84万
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038432
• 关键词: Adhesions; Adhesives; Adoptive Transfer; Behavior; Biochemical; Blocking Antibodies; Blood; Bone Marrow; Cell Adhesion; Cell Communication; Cell Separation; Cell physiology; Cells; Clinic; Clinical; Cues; Data; Defect; Engraftment; Equilibrium; Evaluation; Goals; Health; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; High Dose Chemotherapy; Home environment; Homing; Human; Image; Imaging technology; Immunologic Deficiency Syndromes; Integrins; KAI1 gene; Knockout Mice; Knowledge; Measurement; Measures; Mediating; Membrane; Molecular; Mus; Pancytopenia; Patients; Post-Translational Protein Processing; Property; Proteins; Regenerative Medicine; Regulation; Research; Resolution; Role; Sampling; Scaffolding Protein; Signal Transduction; Site; Stem cell transplant; Stem cells; Testing; Transplantation; Work; base; combinatorial; density; expectation; experience; extracellular; imaging modality; improved; in vivo; innovation; migration; molecular scale; mouse model; nanoscale; new therapeutic target; novel; research study; self-renewal; single molecule; stem; success; therapeutic target; trafficking

 DESCRIPTION (provided by applicant): Hematopoietic stem/progenitor cell (HSPC) communication with the cellular microenvironment is critical for the regulation of stem cell functions. Despite their essential role in the clinical setting, our current understanding of the molecular cues that regulate the trafficking of HSPCs and their niche interactions remain rudimentary. Therefore, to improve HSPC transplantation as a treatment option for patients, it is critical that we identify the molecules and mechanisms that regulate HSPC adhesion, trafficking and repopulation. The objective of this proposal is to determine how the molecular scaffold protein, CD82, regulates HSPC localization and adhesive interactions with the bone marrow, which directly influences HSPC function. We will test the hypothesis that CD82 modulates HSPC homing, mobilization, and long-term repopulation capacity through the regulation of integrin clustering and niche adhesion. In Specific Aim 1, we will use our experience with super-resolution imaging methods and primary human cells to quantify the molecular distribution of CD82 membrane organization and determine the effects on integrin clustering, cell adhesion and homing. For Specific Aim 2, we will determine how changes in CD82 expression alter bone marrow retention, homing, and long-term repopulation of HSPCs using the CD82KO mice. This contribution is significant because we expect to identify CD82 as a novel therapeutic target to improve HSPC isolations and transplant efficacy in the clinic. Furthermore, the combination of quantitative single molecule and in vivo information that we propose to obtain has not been measured previously and will bring new perspectives to the function of CD82 in HSPC adhesion/signaling. As such, this proposal is innovative because it will apply a combinatorial, experimental approach to the problem of HSPC adhesion, bone marrow trafficking and repopulation. By utilizing mouse models, mutational analysis, super-resolution imaging, and primary patient samples, we will integrate molecular, biochemical and morphological information to obtain a multi-scale understanding of the role of CD82 in regulating HSPC/niche interactions and the a4ß1 integrin.

 描述（由应用提供）：与细胞微环境的造血干/祖细胞（HSPC）通信对于调节干细胞功能至关重要。尽管它们在临床环境中起着至关重要的作用，但我们目前对调节HSPC及其利基相互作用的分子提示的理解仍然是基本的。因此，为了改善HSPC的移植作为患者的治疗选择，至关重要的是，我们必须确定调节HSPC粘合剂，贩运和重摄取的分子和机制。该建议的目的是确定分子支架蛋白CD82如何调节HSPC的定位和与骨髓的粘合性相互作用，这直接影响HSPC功能。我们将通过调节整合素聚类和小甲基粘合剂来调节CD82调节HSPC归巢，动员和长期重生能力的假设。在特定的目标1中，我们将利用我们的经验与超分辨率成像方法和原代人类细胞来量化CD82膜组织的分子分布，并确定对整合素聚类，细胞粘合剂和归巢的影响。对于特定的目标2，我们将确定CD82表达的变化如何使用CD82KO小鼠对HSPC的骨髓保留，归巢和长期重新分类。这种贡献很重要，因为我们希望将CD82鉴定为一种新的治疗靶标，以提高诊所中HSPC的分离和移植效率。此外，我们建议获得的定量单分子和体内信息的组合尚未得到测量，并且将为HSPC粘合剂/信号传导中CD82的功能带来新的视角。因此，该提案具有创新性，因为它将在HSPC粘合剂，骨髓贩运和重新填充的问题上采用组合，实验方法。通过利用小鼠模型，突变分析，超分辨率成像和原发性患者样本，我们将整合分子，生化和形态学信息，以获得对CD82在调节HSPC/NICHE相互作用和A4ß1整合素中CD82作用的多尺度理解。