Stromal Cell Function Following Chemotherapy

化疗后基质细胞功能

• 批准号: 7228099
• 负责人: Laura F. Gibson
• 金额: $ 33.13万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228099
• 关键词: Acute; Address; B-Lymphocytes; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Survival; Cell physiology; Cells; Chemicals; Chemotaxis; Chemotherapy-Oncologic Procedure; Chronic; Condition; Data; Development; Disruption; Dose; Down-Regulation; Engraftment; Evaluation; Experimental Designs; Exposure to; Extracellular Matrix; Failure; Funding; Gelatinase A; Gene Expression; Generations; Hematopoietic; Hematopoietic stem cells; High Dose Chemotherapy; In Vitro; Interruption; Investigation; Knock-out; Marrow; Matrix Metalloproteinases; Mediating; Modeling; Mus; Patients; Phenotype; Pilot Projects; Positioning Attribute; Process; Progress Reports; Proteins; Reactive Oxygen Species; Recombinants; Recovery; Regulation; Research Personnel; Role; Signal Transduction; Small Interfering RNA; Stem cells; Stromal Cell-Derived Factor 1; Stromal Cells; Testing; Transforming Growth Factor beta; Translating; Vascular Cell Adhesion Molecule-1; Work; acute stress; autocrine; base; cell injury; cellular engineering; chemokine; chemotherapy; in vivo; in vivo Model; inhibitor/antagonist; migration; mouse model; protein expression; reconstitution; research study; response; tumor eradication

DESCRIPTION (provided by applicant): Dose escalated chemotherapy regimens are now known to damage cells of the hematopoietic microenvironment. Work completed during the previous period of funding demonstrated that exposure of bone marrow stromal cells to VP-16 resulted in reduced ability to support migration and survival of hematopoietic progenitor cells. During the recent period of funding, we also demonstrated that VP-16 exposure altered expression and activity of stromal cell matrix metalloproteinase-2 (MMP-2). Acute exposure to VP-16 resulted in immediate, transient activation of pro-MMP-2 protein. In contrast, long-term exposure resulted in down regulation of MMP-2 protein expression. The varied responses to acute and chronic exposure on MMP-2 have distinct consequences on stromal cell function. Activation of MMP-2 was correlated with release of TGF-beta, which has potential to alter stromal cell phenotype and function in an autocrine manner. Reduced MMP-2 protein expression, associated with sustained exposure of stromal cells to VP-16, resulted in diminished SDF-1 protein in stromal cell supernatants and failure of chemotactic support of hematopoietic cells. These studies underscore a role for MMP-2 in influencing the bone marrow microenvironment that exceeds its well-characterized function in extracellular matrix regulation. The current application will address the mechanism(s) by which chemotherapy-induced effects on MMP-2 alter obligatory components of the hematopoietic microenvironment through completion of the following specific aims: (1) to evaluate the autocrine effects of MMP-2-dependent TGF-beta release on stromal cell hematopoietic support capacity, (2) to investigate the mechanisms by which diminished MMP-2 reduces stromal cell support of chemotaxis, and (3) to develop a murine in vivo model to investigate the effects of modulation of chemotherapy induced-signaling to enhance bone marrow microenvironment support of hematopoietic reconstitution. Our working hypothesis is that inefficient hematopoietic reconstitution following VP-16 chemotherapy is, in part, due to deregulated activation and expression of stromal cell MMP-2 protein. Results of these experiments will aid in tailoring high dose chemotherapy regimens to maintain efficacy of tumor eradication while reducing microenvironment damage to the hematopoietic microenvironment.

描述（由申请人提供）：现在已知剂量递增的化疗方案会损害造血微环境的细胞。上一资助期间完成的工作表明，骨髓基质细胞暴露于 VP-16 会导致支持造血祖细胞迁移和存活的能力降低。在最近的资助期间，我们还证明了 VP-16 暴露改变了基质细胞基质金属蛋白酶-2 (MMP-2) 的表达和活性。急性暴露于 VP-16 会导致 pro-MMP-2 蛋白立即、瞬时激活。相反，长期暴露会导致 MMP-2 蛋白表达下调。对 MMP-2 的急性和慢性暴露的不同反应对基质细胞功能具有不同的影响。 MMP-2 的激活与 TGF-β 的释放相关，TGF-β 具有以自分泌方式改变基质细胞表型和功能的潜力。 MMP-2 蛋白表达减少与基质细胞持续暴露于 VP-16 相关，导致基质细胞上清液中 SDF-1 蛋白减少，造血细胞趋化支持失败。这些研究强调了 MM​​P-2 在影响骨髓微环境方面的作用，其作用超出了其在细胞外基质调节中的明确功能。当前的申请将通过完成以下具体目标来解决化疗诱导的 MMP-2 效应改变造血微环境的必要组成部分的机制：(1) 评估 MMP-2 依赖性 TGF 的自分泌效应-β 释放对基质细胞造血支持能力的影响，(2) 研究 MMP-2 减少减少基质细胞趋化性支持的机制，以及 (3) 开发一种小鼠体内模型研究化疗诱导信号调节对增强骨髓微环境支持造血重建的影响。我们的工作假设是，VP-16 化疗后造血重建效率低下部分是由于基质细胞 MMP-2 蛋白的激活和表达失调所致。这些实验的结果将有助于调整高剂量化疗方案，以维持肿瘤根除的功效，同时减少对造血微环境的损害。