Chondrogenesis In Situ

原位软骨形成

• 批准号: 7883452
• 负责人: CONSTANCE R CHU
• 金额: $ 40.45万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883452
• 关键词: Adult; Animal Model; Animals; Arthroscopy; Bone Marrow; Bone Marrow Cells; Cartilage; Cartilage injury; Cells; Chondrogenesis; Clinical Pathways; Clinical assessments; Confocal Microscopy; Data; Defect; Dependovirus; Dominant-Negative Mutation; Down-Regulation; Environment; Gene Expression; Gene Expression Regulation; Genes; Goat; Growth Factor; Homeostasis; Human; Imaging technology; In Situ; In Vitro; Joints; Modality; Modeling; Nude Rats; Optical Coherence Tomography; Pattern; Polyethylene Glycols; Polymers; Public Health; Publications; Rattus; Research Personnel; Scientist; Signal Transduction; Site; Spatial Distribution; System; Technology; Testing; Tetanus Helper Peptide; Translations; Up-Regulation; Virus; articular cartilage; cartilage repair; controlled release; crosslink; disability; gene therapy; genipin; human TGFB1 protein; implantation; improved; in vivo; innovation; miniaturize; multidisciplinary; novel; osteochondral repair; osteochondral tissue; pre-clinical; programs; receptor; repaired; response; scaffold; transgene expression; vector

DESCRIPTION (provided by applicant): Articular cartilage injury and degeneration are leading causes of disability [1, 2]. Accessing bone marrow cells for cartilage repair through microfracture is commonly performed clinically. However, the frequently fibrous repairs yield mixed results [3, 4]. Safe, localized in vivo use of bioactive factors to improve chondrogenesis in situ of human bone marrow cells (BMC) for cartilage repair therefore has compelling public health impacts. Transforming growth factor-beta-1 (TGF-b1) consistently induces chondrogenesis of hBMC [5, 6]. Major challenges for in vivo administration of TGF-b1 include controlling and containing TGF-b1 effects. TGF-b signaling through its type II receptor (TbR-ll) is important to cellular responsiveness to TGF-b and to cartilage homeostasis [7]. Using chondrogenesis as the desired endpoint, we propose to study an intriguing question as to whether the pattern of TbR-II expression, in particular sustained TbR-II expression, is the mechanism that determines whether bone marrow cells will undergo chondroid differentiation in vivo. The central hypothesis of this proposal is that sustained upregulation of TbR-ll is necessary for in vivo chondrogenesis of bone marrow cells and that this can be achieved through sustained administration of TGF-B1. The specific aims of this proposal are: 1. To test the hypothesis that sustained upregulation of TbR-II is necessary for chondrogenesis of adult human BMC in vivo, within the diarthrodial environment. 2. To test the hypothesis that controlled release of TGF-b1 from genipin crosslinked polyethylene glycol (PEG-genipin) scaffolds will induce localized, sustained in vivo TbR-ll upregulation, chondrogenesis of host bone marrow cells (BMC), and improve osteochondral repair with minimal joint effects. 3. To test the hypothesis that highly localized, stable and regulatable TGF-b1 gene expression in diarthrodial joints can be achieved by adeno-associated virus (AAV)-TGF-b vectors that are gradually released from PEG-genipin scaffolds. Such gene expression is anticipated to induce localized in vivo upregulation of TbR-ll, chondrogenesis of host bone marrow repair cells, and improve osteochondral repair with minimal joint effects. The unique translational aspects of this proposal include (1) a Clinician-Scientist led multidisciplinary team to optimize related but independent strategies for localized, controlled in vivo delivery of growth factors to improve the cartilage repair potential of bone marrow cells; and (2) provision of a direct pathway for clinical translation of innovative scaffold technology and controlled gene therapy to improve cartilage repair, and the arthroscopic use of novel nondestructive advanced cartilage imaging technologies.

描述（申请人提供）：关节软骨损伤和退变是致残的主要原因[1,2]。通过微骨折获取骨髓细胞进行软骨修复是临床上常用的方法。然而，纤维修复经常产生混合结果[3,4]。因此，安全、局部地在体内使用生物活性因子来改善人骨髓细胞原位软骨形成（BMC）以进行软骨修复具有引人注目的公共卫生影响。转化生长因子- β -1 （TGF-b1）持续诱导hBMC的软骨形成[5,6]。体内给药TGF-b1的主要挑战包括控制和抑制TGF-b1的作用。TGF-b信号通过其II型受体（TbR-ll）传导，对于细胞对TGF-b的反应和软骨稳态bbb非常重要。以软骨形成为预期终点，我们提出研究一个有趣的问题，即TbR-II的表达模式，特别是持续的TbR-II表达，是否是决定骨髓细胞是否会在体内发生软骨样分化的机制。该建议的中心假设是，持续上调tbr - 1对于体内骨髓细胞的软骨形成是必要的，这可以通过持续给药TGF-B1来实现。本建议的具体目的是：1。为了验证在体内，在腹泻环境下，持续上调TbR-II对于成人BMC的软骨形成是必要的假设。2. 为了验证从genipin交联聚乙二醇（PEG-genipin）支架中控制TGF-b1的释放将诱导局部、持续的体内tbr - 1上调，宿主骨髓细胞（BMC）的软骨形成，并以最小的关节效应改善骨软骨修复的假设。3. 通过腺相关病毒（adeno-associated virus， AAV）-TGF-b载体从PEG-genipin支架中逐渐释放，可以实现高定位、稳定和可调节的TGF-b1基因在关节内的表达。这种基因表达有望诱导体内TbR-ll的局部上调，促进宿主骨髓修复细胞的软骨形成，并以最小的关节效应改善骨软骨修复。该提案的独特转化方面包括：(1)由临床医生-科学家领导的多学科团队优化相关但独立的策略，用于局部控制生长因子的体内递送，以提高骨髓细胞的软骨修复潜力；(2)为创新支架技术的临床转化和控制基因治疗提供直接途径，以改善软骨修复，并在关节镜下使用新型无损的先进软骨成像技术。