Chondrogenesis In Situ

原位软骨形成

• 批准号: 8799194
• 负责人: CONSTANCE R CHU
• 金额: $ 4.45万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 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 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8799194
• 关键词: Chondrogenesis; Situ

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）：关节软骨损伤和退化是导致残疾的主要原因[1，2]。临床上常使用骨髓细胞通过微骨折进行软骨修复。然而，频繁的纤维修复产生混合结果[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（BMC）的原位软骨形成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-β 1）持续诱导hBMC的软骨形成[5，6]。体内施用TGF-β 1的主要挑战包括控制和抑制TGF-β 1的作用。通过其II型受体（TbR-II）的TGF-β信号传导对于细胞对TGF-β的反应性和软骨稳态是重要的[7]。使用软骨形成作为所需的终点，我们建议研究一个有趣的问题，是否TbR-II的表达模式，特别是持续TbR-II的表达，是决定是否骨髓细胞将在体内进行软骨样分化的机制。该提议的中心假设是TbR-II的持续上调对于骨髓细胞的体内软骨形成是必要的，并且这可以通过持续给予TGF-B1来实现。该提案的具体目标是：1.为了验证TbR-II的持续上调是体内成人BMC在关节环境中软骨形成所必需的假设。2.为了测试以下假设：从京尼平交联的聚乙二醇（PEG-京尼平）支架中控制释放TGF-β 1将诱导局部的、持续的体内TbR-II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。3.为了验证这一假设，即高度定位，稳定和可调控的TGF-β 1基因表达的关节可以实现腺相关病毒（AAV）-TGF-β载体，逐渐释放的PEG-京尼平支架。预计这种基因表达会诱导TbR-II的体内局部上调、宿主骨髓修复细胞的软骨形成，并在最小关节影响的情况下改善骨软骨修复。该提案的独特转化方面包括（1）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，用于生长因子的局部、受控体内递送，以改善骨髓细胞的软骨修复潜力;和（2）为创新支架技术和受控基因治疗的临床转化提供直接途径，以改善软骨修复，以及新型非破坏性先进软骨成像技术的关节镜使用。

项目成果

Sustained hypoxia enhances chondrocyte matrix synthesis.

• DOI: 10.1002/jor.20816
• 发表时间: 2009-06
• 期刊: Journal of orthopaedic research : official publication of the Orthopaedic Research Society
• 作者: Coyle CH;Izzo NJ;Chu CR
• 通讯作者: Chu CR

The effect of platelet-rich plasma formulations and blood products on human synoviocytes: implications for intra-articular injury and therapy.

• DOI: 10.1177/0363546514525593
• 发表时间: 2014-05
• 期刊: The American journal of sports medicine
• 作者: Braun HJ;Kim HJ;Chu CR;Dragoo JL
• 通讯作者: Dragoo JL

The Clinical Use of Human Culture-Expanded Autologous Bone Marrow Mesenchymal Stem Cells Transplanted on Platelet-Rich Fibrin Glue in the Treatment of Articular Cartilage Defects: A Pilot Study and Preliminary Results.

• DOI: 10.1177/1947603510366027
• 发表时间: 2010-10
• 期刊: Cartilage
• 影响因子: 2.8
• 作者: Haleem AM;Singergy AA;Sabry D;Atta HM;Rashed LA;Chu CR;El Shewy MT;Azzam A;Abdel Aziz MT
• 通讯作者: Abdel Aziz MT

Injectable in situ forming biodegradable chitosan-hyaluronic acid based hydrogels for cartilage tissue engineering.

• DOI: 10.1016/j.biomaterials.2008.12.080
• 发表时间: 2009-05
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Tan, Huaping;Chu, Constance R.;Payne, Karin A.;Marra, Kacey G.
• 通讯作者: Marra, Kacey G.

Donor sex and age influence the chondrogenic potential of human femoral bone marrow stem cells.

• DOI: 10.1016/j.joca.2010.01.011
• 发表时间: 2010-05
• 期刊: OSTEOARTHRITIS AND CARTILAGE
• 影响因子: 7
• 作者: Payne, K. A.;Didiano, D. M.;Chu, C. R.
• 通讯作者: Chu, C. R.