Chondrogenesis In Situ

原位软骨形成

基本信息

批准号：
8073319
负责人：
CONSTANCE R CHU
金额：
$ 2.13万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-20 至 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8073319
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

项目摘要

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（由申请人提供）：关节软骨损伤和变性是残疾的主要原因[1，2]。通常在临床上进行微骨修复软骨修复的骨髓细胞。但是，经常纤维修复会产生混合的结果[3，4]。安全，局部的体内使用生物活性因子以改善人体骨髓细胞（BMC）进行软骨修复的原位，因此具有令人信服的公共卫生影响。转化生长因子-BETA-1（TGF-B1）始终诱导HBMC的软骨形成[5，6]。体内给药TGF-B1的主要挑战包括控制和包含TGF-B1效应。通过其II型受体（TBR-LL）的TGF-B信号传导对于细胞对TGF-B和软骨稳态的反应至关重要[7]。我们提出，将软骨发生作为所需的终点，研究一个有趣的问题，即TBR-II表达的模式，尤其是持续的TBR-II表达，是确定骨髓细胞是否会在体内进行软骨细胞分化的机制。该提议的中心假设是，TBR-LL的持续上调对于骨髓细胞的体内软骨形成是必要的，并且可以通过持续的TGF-B1施用来实现这一点。该提议的具体目的是：1。检验以下假设：在腹膜内环境中，TBR-II的持续上调对于成年人类BMC的软骨形成是必要的。 2。为了检验以下假设：控制TGF-B1从Genipin交联的聚乙烯甘氨酸（PEG-烯磷酸）支架中释放将诱导本地化，持续的体内TBR-LLL上调，软骨上调，宿主骨髓细胞（BMC）的软骨形成，并改善骨软骨核心修复，并改善骨软骨关节效应。 3。为了测试以下假设：腹泻关节中高度局部，稳定和可调节的TGF-B1基因表达可以通过腺相关病毒（AAV）-TGF-B载体来逐渐从PEG-Genipin支架中释放出来。预计这种基因表达会诱导TBR-LL的体内上调，宿主骨髓修复细胞的软骨形成，并改善骨软骨修复，而关节效应最小。该提案的独特翻译方面包括（1）临床医生科学家带领多学科团队优化了相关但独立的策略，用于局部，受控的体内生长因子的局部，以提高骨髓细胞的软骨修复潜力；（2）提供创新脚手架技术和受控基因疗法临床翻译的直接途径，以改善软骨修复以及关节镜使用新型无损的高级软骨成像技术。