CSF-1 Gene Expression in Osteoclast Biology

破骨细胞生物学中的 CSF-1 基因表达

• 批准号: 7268843
• 负责人: SHERRY L ABBOUD-WERNER
• 金额: $ 21.32万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268843
• 关键词: Address; Adenovirus Vector; Angiogenic Factor; Animal Model; Arthritis; Attenuated; Binding; Biology; Bone and Cartilage Funding; Cartilage injury; Chimeric Proteins; Clinical; Collagen Arthritis; Collagen Type II; Combined Modality Therapy; Complementary DNA; Data; Disease; Disease Progression; Endothelial Cells; FUS-1 Protein; Factor VIII-Related Antigen; Future; Gene Expression; Genes; Genetic Recombination; Goals; Growth Factor; Histologic; Human; Hyperplasia; Immune Sera; In Vitro; Incidence; Injection of therapeutic agent; Injury; Joints; Knee joint; Knock-in Mouse; Knock-out; LacZ Genes; Lead; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Mediating; Membrane; Mesenchymal Stem Cells; Messenger RNA; Methods; Modeling; Mus; Osteitis; Osteoclasts; PECAM1 gene; Pathologic; Patients; Play; Protein Isoforms; Proteins; Recombinants; Research Personnel; Resolution; Retroviral Vector; Rheumatoid Arthritis; Role; Serum; Severities; Staining method; Stains; Synovial Fluid; Therapeutic; Therapeutic Intervention; Time; Tissues; Transgenic Mice; Treatment Efficacy; VWF gene; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; angiogenesis; base; bone; bone turnover; density; design; gene therapy; inhibitor/antagonist; monocyte; mouse model; neovascularization; novel; novel strategies; osteoclastogenesis; prevent; programs; promoter; receptor; selective expression; tumor; von Willebrand Factor; Address; Adenovirus Vector; Angiogenic Factor; Animal Model; Arthritis; Attenuated; Binding; Biology; Bone and Cartilage Funding; Cartilage injury; Chimeric Proteins; Clinical; Collagen Arthritis; Collagen Type II; Combined Modality Therapy; Complementary DNA; Data; Disease; Disease Progression; Endothelial Cells; FUS-1 Protein; Factor VIII-Related Antigen; Future; Gene Expression; Genes; Genetic Recombination; Goals; Growth Factor; Histologic; Human; Hyperplasia; Immune Sera; In Vitro; Incidence; Injection of therapeutic agent; Injury; Joints; Knee joint; Knock-in Mouse; Knock-out; LacZ Genes; Lead; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Mediating; Membrane; Mesenchymal Stem Cells; Messenger RNA; Methods; Modeling; Mus; Osteitis; Osteoclasts; PECAM1 gene; Pathologic; Patients; Play; Protein Isoforms; Proteins; Recombinants; Research Personnel; Resolution; Retroviral Vector; Rheumatoid Arthritis; Role; Serum; Severities; Staining method; Stains; Synovial Fluid; Therapeutic; Therapeutic Intervention; Time; Tissues; Transgenic Mice; Treatment Efficacy; VWF gene; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; angiogenesis; base; bone; bone turnover; density; design; gene therapy; inhibitor/antagonist; monocyte; mouse model; neovascularization; novel; novel strategies; osteoclastogenesis; prevent; programs; promoter; receptor; selective expression; tumor; von Willebrand Factor

DESCRIPTION (provided by applicant): Macrophage colony stimulating factor (CSF-1) is essential for the formation of osteoclasts that, in turn, regulate bone turnover. The long-term goal of this proposal is to determine the role of CSF-1 in osteoclast- and monocyte-mediated bone and cartilage destruction in rheumatoid arthritis (RA) using animal models and whether inhibition of CSF-1 alone or in combination with vascular endothelial growth factor (VEGF) ameliorates the disease. Recently, we identified a -3.3 kb/+183 bp region of the CSF-1 promoter that confers lacZ expression in joint tissues of transgenic mice which will be useful for targeting exogenous genes to joint tissue. Our hypothesis is that CSF-1 acts in concert with VEGF, an angiogenic factor that promotes pannus expansion, to enhance cartilage and bone destruction in RA. Patients with RA show increased levels of CSF-1 and VEGF in synovial tissues and serum. However, whether the soluble (s) and membrane-bound (m) forms of CSF-1 mediate distinct biologic effects in RA is unknown. To address this issue, we will use a knock-out and high throughput knock-in approach to selectively express sCSF-1 or mCSF-1 in mice and examine their effect in collagen-induced arthritis (CIA), a model that mimics the human counterpart of RA. Optimal management of RA would require inhibition of synovial hyperplasia, cartilage and bone destruction. Our plan is to inhibit CSF-1 and VEGF in the joint microenvironment using soluble CSF-1 receptor (CSF-1 R) and soluble VEGF receptor (FLT-1), thereby preventing the onset and/or ameliorating established arthritis. The efficacy of osteoclast antagonists in combination with anti-angiogenic factors in RA has not been explored. For these studies, transgenic mice carrying the CSF-1 R under the control of the -3.3 kb/+183 bp CSF-1 promoter will be generated and assessed for clinical and histologic severity of CIA. The effect of combined treatment with FLT-1 in CIA will be determined by delivering FLT-1 to the joints of CSF-1 R transgenic mice using adenoviral and retroviral based approaches. These studies should elucidate the role of CSF-1 isoforms and the therapeutic efficacy of inhibiting osteoclast activity and angiogenesis in rheumatoid arthritis and perhaps, identify novel strategies for therapeutic intervention in this disorder.

描述（由申请人提供）：巨噬细胞刺激因子（CSF-1）对于形成破骨细胞的必不可少，而破骨细胞又调节了骨骼更新。该提案的长期目标是使用动物模型在类风湿关节炎（RA）中确定CSF-1在骨细胞和单核细胞介导的骨和软骨破坏中的作用，以及是否仅抑制CSF-1，还是抑制血管内皮细胞生长因子（VEVGF）可改善疾病。最近，我们确定了CSF -1启动子的-3.3 kb/+183 bp区域，该区域赋予了转基因小鼠关节组织中的LACZ表达，这将有助于将外源基因靶向关节组织。我们的假设是，CSF-1与VEGF共同起作用，VEGF是一种促进Pannus膨胀的血管生成因子，以增强RA的软骨和骨骼破坏。 RA患者在滑膜组织和血清中表现出CSF-1和VEGF的水平升高。但是，CSF-1的可溶性（S）和膜结合（M）形式是否介导了RA中不同的生物学效应。为了解决这个问题，我们将使用一种敲除且高吞吐量的敲门方法在小鼠中有选择地表达SCSF-1或MCSF-1，并检查它们在胶原蛋白诱导的关节炎（CIA）中的作用，该模型模拟了RA的人类对应物。 RA的最佳管理将需要抑制滑膜增生，软骨和骨骼破坏。我们的计划是使用可溶性CSF-1受体（CSF-1 R）和可溶性VEGF受体（FLT-1）抑制关节微环境中的CSF-1和VEGF，从而防止了开始和/或改善已建立的关节炎。尚未探索破骨细胞拮抗剂与RA中抗血管生成因子结合使用的功效。对于这些研究，将生成并评估CIA的临床和组织学严重程度，并评估携带CSF-1 R的转基因小鼠。使用基于腺病毒和逆转录病毒的方法将FLT-1与CSF-1 R转基因小鼠的关节交付给CSF-1 R转基因小鼠的关节来确定CIA中FLT-1联合治疗的效果。这些研究应阐明CSF-1同工型的作用以及抑制破骨细胞活性和血管生成在类风湿关节炎中的治疗功效，并可能确定这种疾病中治疗干预的新策略。