Targeting Pathological Angiogenesis after Joint Injury

针对关节损伤后的病理性血管生成

• 批准号: 10214725
• 负责人: ANDREA I ALFORD
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214725
• 关键词: Acute; Address; Adenoviruses; Adult; Affect; Angiogenesis Inhibitors; Angiogenic Factor; Anti-Inflammatory Agents; Attenuated; Biological Availability; Biological Process; Biomedical Engineering; Blood Vessels; Cartilage; Catabolism; Cell Survival; Cells; Chimera organism; Chondrocytes; Chronic; Collagen; Data; Degenerative polyarthritis; Development; Diagnosis; Disease; Disease Progression; Doctor of Philosophy; Endothelial Cells; Exhibits; Extracellular Matrix; Fibroblasts; Fracture Healing; Future; Gene Transfer; Health; Histology; Human; Hyperplasia; Hypertrophy; Image; Inflammation; Inflammatory; Injury; Joints; Knock-out; Literature; Lymphoid; Matrix Metalloproteinases; Measures; Mesenchymal; Methodology; Minerals; Molecular; Mus; Pain; Pathogenesis; Pathologic; Pathologic Neovascularization; Pathway interactions; Patients; Peptide Hydrolases; Physiologic Ossification; Population; Process; Property; Proteins; Research; Research Personnel; Rheumatism; Rheumatoid Arthritis; Role; Severities; Structure; Synovial Cell; Synovial Membrane; Synovitis; THBS2 gene; Testing; Therapeutic; Time; Tissues; Up-Regulation; Vascular Endothelial Growth Factors; Vascularization; Work; angiogenesis; arthropathies; base; blood vessel development; bone; cell type; chemokine; cytokine; effective therapy; experimental study; histological image; injured; innovation; joint destruction; joint inflammation; joint injury; molecular imaging; novel; osteochondral tissue; overexpression; prevent; response; single-cell RNA sequencing; thrombospondin 2; transcriptome sequencing

ABSTRACT INVESTIGATORS: Tristan Maerz, PhD (PI) is a biomedical engineer and early-stage investigator focused on joint injury and post-traumatic osteoarthritis (PTOA). Andrea Alford, PhD (Co-PI) is a matrix biologist focused on the interactions of matricellular proteins, the extracellular matrix, and cells. Together, they have extensive complementary expertise to study the role of thrombospondin-2 in PTOA using innovative methodologies. RESEARCH CONTEXT: PTOA accounts for ~12% of osteoarthritis cases, constituting ~5.6 million sympto- matic cases in the US. Synovitis is now increasingly recognized as a perpetuator of joint degeneration, analo- gous to its role in rheumatic diseases. Alongside inflammation is increased angiogenesis, which promotes in- flammation and tissue catabolism by increasing vascular access to inflammatory cells and cytokines within the joint. However, no study has demonstrated whether modulating the degree of angiogenesis affects intraarticu- lar inflammation and downstream PTOA severity after joint injury. Thrombospondin-2 (TSP2) is an endogenous anti-angiogenic factor, and this proposal’s preliminary data demonstrates that it is markedly upregulated in the synovium following joint injury, making it a potential regulator of intraarticular angiogenesis and PTOA. SPECIFIC AIMS: 1). Determine the extent to which temporal TSP2 knockout at the time of injury increases an- giogenesis, synovitis, and PTOA severity. 2). Assess the anti-angiogenic, anti-inflammatory, and PTOA-miti- gating effect of intraarticular TSP2 gene transfer. RESEARCH PLAN: In Aim 1, single-cell RNAseq will be used to profile TSP2(+) synovial cell populations and associated angiogenic pathways. A global, inducible Rosa26-CreERT2;TSP2flox mouse will then be used to ab- late TSP2 to assess the extent to which increased intraarticular angiogenesis affects synovitis, matrix metallo- proteinase (MMP) activity (assessed using molecular imaging), pain and function, and histological and imag- ing-based PTOA severity. In Aim 2, adenoviral TSP2 will be administered intraarticularly to both WT and Rosa26-CreERT2;TSP2flox mice after joint injury, and the downstream effect on intraarticular angiogenesis, synovitis, MMP activity, pain and function, chondrocyte hypertrophy, and PTOA severity will be assessed to elucidate whether TSP2 can be employed as a disease-modifying therapeutic. INNOVATION: Demonstrating a relationship between the degree of post-injury angiogenesis and PTOA sever- ity would be a high-impact finding by identifying a potentially-modifiable acute process that affects PTOA path- ogenesis. While TSP2’s anti-angiogenic role has been studied extensively in fracture healing, little to no litera- ture has elucidated its role in the synovium and in the context of PTOA. Lastly, this proposal aims to use sev- eral innovative imaging methodologies to characterize joint catabolism and PTOA severity, providing a poten- tial translational path for earlier, more sensitive PTOA and OA diagnosis using innovative imaging.

抽象的 研究人员：Tristan Maerz博士（PI）是一名生物医学工程师和早期研究人员 关节损伤和创伤后骨关节炎（PTOA）。 Andrea Alford，博士（CO-PI）是基质生物学家 关于基质蛋白，细胞外基质和细胞的相互作用。他们在一起有广泛的 完全专业的知识，可以使用创新方法研究血小板传播-2在PTOA中的作用。 研究环境：PTOA占骨关节炎病例的约12％，构成约560万个症状 - 美国的案件。滑膜炎现在越来越多地被认为是关节变性的永久剂 与其在风湿性疾病中的作用有关。在炎症的旁边是血管生成增加，这促进了 通过增加血管内炎性细胞和细胞因子的血管和组织分解代谢 联合的。然而，尚无研究表明调节血管生成程度是否会影响ArtaIrticu- 关节损伤后，LAR炎症和下游PTOA严重程度。血小板传播-2（TSP2）是内源性的 抗血管生成因素，该提案的初步数据表明，它在 关节损伤后的滑膜，使其成为关节内血管生成和PTOA的潜在调节剂。 具体目的：1）。确定受伤时暂时的TSP2敲除的程度增加 Giogenesogeny，滑膜炎和PTOA严重程度。 2）。评估抗血管生成，抗炎和PTOA-MITI- 关节内TSP2基因转移的门控效应。 研究计划：在AIM 1中，单细胞RNASEQ将用于介绍TSP2（+）滑细胞群体和 相关的血管生成途径。然后，将使用一种全局的，可诱导的Rosa26-Creert2; TSP2Flox小鼠 TSP2晚期以评估关节内血管生成增加的程度会影响滑膜炎，基质金属 - 蛋白酶（MMP）活性（使用分子成像评估），疼痛和功能以及组织学和成像 基于ING的PTOA严重性。在AIM 2中，腺病毒TSP2将在WT和 关节损伤后的rosa26-creert2; tsp2flox小鼠，以及对关节内血管生成的作用， 滑膜炎，MMP活性，疼痛和功能，软骨细胞肥大和PTOA严重程度将评估为 阐明是否可以将TSP2用作调整疾病的治疗。 创新：证明伤害后血管生成程度与PTOA的关系之间的关系 通过确定影响PTOA路径的潜在可修改的急性过程，这将是一个高影响的发现。 尽管TSP2的抗血管生成作用已在骨折愈合中广泛研究，但几乎没有文献 - Ture阐明了其在滑膜和PTOA背景下的作用。最后，该提议旨在使用SEV- ERA创新成像方法以表征联合分解代谢和PTOA严重性，提供有效的 使用创新成像的早期，更灵敏的PTOA和OA诊断的TIAL翻译路径。