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

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（由申请方提供）：巨噬细胞集落刺激因子（CSF-1）对破骨细胞的形成至关重要，破骨细胞反过来又调节骨转换。本提案的长期目标是使用动物模型确定CSF-1在类风湿性关节炎（RA）中破骨细胞和单核细胞介导的骨和软骨破坏中的作用，以及单独抑制CSF-1或与血管内皮生长因子（VEGF）组合抑制CSF-1是否改善疾病。最近，我们鉴定了CSF-1启动子的-3.3kb/+183bp区域，其赋予lacZ在转基因小鼠的关节组织中的表达，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（一种促进血管翳扩张的血管生成因子）协同作用，以增强RA的软骨和骨破坏。RA患者滑膜组织和血清中CSF-1和VEGF水平升高。然而，尚不清楚CSF-1的可溶性和膜结合形式是否介导RA中不同的生物学效应。为了解决这个问题，我们将使用敲除和高通量敲入方法在小鼠中选择性表达sCSF-1或mCSF-1，并检查它们在胶原诱导的关节炎（CIA）中的作用，CIA是一种模拟人类RA的模型。RA的最佳管理需要抑制滑膜增生、软骨和骨破坏。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，从而预防和/或改善已建立的关节炎。破骨细胞拮抗剂联合抗血管生成因子治疗RA的疗效尚未探讨。对于这些研究，将产生在-3.3 kb/+183 bp CSF-1启动子控制下携带CSF-1 R的转基因小鼠，并评估CIA的临床和组织学严重程度。通过使用基于腺病毒和逆转录病毒的方法将FLT-1递送至CSF-1 R转基因小鼠的关节来确定与FLT-1联合治疗CIA的效果。这些研究应阐明CSF-1亚型的作用和抑制破骨细胞活性和血管生成在类风湿性关节炎的治疗效果，也许，确定新的策略，在这种疾病的治疗干预。