BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10047721
• 负责人: KAREN A. HASTY
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047721
• 关键词: Acceleration; Adipose tissue; Advanced Development; Affect; Animal Model; Animals; Antibodies; Architecture; Area; Arthritis; Arthroscopy; Avidin; Award; Binding; Biotin; Bone Marrow; Bone Marrow Stem Cell; Cartilage; Cartilage Matrix; Cartilage injury; Cells; Chondrocytes; Chronic; Clinical Trials; Collagen Arthritis; Collagen Type II; Coupled; Data; Defect; Deformity; Degenerative polyarthritis; Detection; Development; Diagnosis; Disease; Disease Progression; Doctor of Philosophy; Domestic Pig; Drug Delivery Systems; Drug Evaluation; Early Diagnosis; Early treatment; Encapsulated; Euthanasia; Evaluation; Family suidae; Funding; Future; Gene Expression; Glycoproteins; Goals; Histopathology; Human; Image; Immune; Immunologics; Incidence; Individual; Inflammation; Inflammatory Arthritis; Injury; Intra-Articular Injections; Investigational Therapies; Joints; Knee; Lesion; Ligands; Link; Liposomes; Longitudinal Studies; Matrix Metalloproteinases; Measures; Mechanical Stress; Mechanics; Meniscus structure of joint; Mesenchymal Stem Cells; Methods; Military Personnel; Modeling; Monitor; Monoclonal Antibodies; NF-kappa B; Occupational; Occupations; Operative Surgical Procedures; Optics; Oryctolagus cuniculus; Pain; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Play; Polymers; Population; Prevalence; Prevention; Procedures; Production; Proteins; Proteoglycan; Quality of life; Reconstructive Surgical Procedures; Regulation; Rehabilitation therapy; Replacement Arthroplasty; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Rhubarb food; Risk; Role; Scanning; Scientist; Site; Small Interfering RNA; Solid; Surface; Surgical Models; System; Techniques; Therapeutic Intervention; Thick; Time; Tissues; Traumatic injury; Treatment Efficacy; Veterans; Weight-Bearing state; age related; animal tissue; antibody test; arthropathies; articular cartilage; career; cartilage degradation; cartilage repair; cell injury; collagenase 3; disability; improved; in vivo; inhibitor/antagonist; innovation; interest; joint destruction; joint inflammation; joint injury; loss of function; macrophage; meniscus injury; military veteran; mouse model; nanomedicine; nanoparticle; novel; prevent; programs; recruit; repaired; screening; stem cells; subchondral bone; targeted treatment; theranostics; tool; treatment planning

Arthritis is the nation's leading cause of disability. Patients with a previous joint injury are at risk for early development of post-traumatic osteoarthritis (PTOA) even with reconstructive surgery. PTOA is seen in younger patients than age-related osteoarthritis and it has a higher incidence in populations that have high physical occupational demands (i.e., military personnel). Currently, PTOA treatment is primarily for pain until joints fail and joint replacement surgery, an expensive treatment associated with a long rehabilitation. The overall goal of my research is to develop a targeted nanomedicine that can halt cartilage degeneration, improve quality of life and reduce the need for joint replacement in patients. The ability to detect early cartilage damage in traumatic injury or degenerative arthritis has been limited, preventing treatment when therapies may be more beneficial. Depletion of proteoglycans/glycoproteins on the surface of the cartilage in these disorders results in unmasking of the underlying type II collagen (CII). This allows CII to serve as an immunologically recognizable target for monoclonal antibody to type II collagen (MabCII). Fluorescent MabCII can be used for diagnosis of cartilage injury or degeneration or MabCII coupled to nanosomes can target encapsulated drugs for localized delivery to the cartilage lesion. Our preliminary evidence shows a similar strategy can target and recruit reparative chondrocytes or mesenchymal stem cells to the damaged site. Thus, MabCII is used in a comprehensive treatment plan for directing reparative cells to lesions of the articular cartilage and meniscal cartilages and monitoring this by an innovative fluorescent arthroscopy. In addition, recruitment and integration of the reparative cells in the cartilage lesions is optimized by reducing matrix metalloproteinases (MMP) production in the joint by intra-articular injection of a pharmacological inhibitor of the activation of the nuclear factor kappa B (NF-KB) pathway encapsulated in MabCII-targeted nanosomes. These procedures are extremely novel and paradigm shifting for the diagnosis and treatment of joint injury and disease. I am using them for: (1) early diagnosis of damaged and degenerative areas of articular surface and meniscal cartilages in the pig knee using a sensitive, MabCII antibody-guided method of fluorescent arthroscopy (FA). Our PTOA model uses surgically-induced injuries to meniscal and articular cartilages in the knee of the domestic pig. The pig knee closely resembles a human joint in size, weight-bearing requirements and cartilage thickness. The damage is visualized through its binding to fluorescent MabCII using fluorescent arthroscopy, a new procedure that we have developed, and confirmed by histopathology. After FA characterization of the injury, (2) reparative cells are targeted to the area of damaged cartilages in the knee with MabCII antibody. We are investigating the therapeutic efficacy of fluorescent, MabCII-targeted chondrocytes or mesenchymal stem cells derived from bone marrow and adipose tissues intra-articularly injected into joints where articular or meniscal cartilages have been surgically damaged monitoring the cellular localization and persistence by FA. Cell to cell recruitment at the cartilage lesion in the knee is facilitated by an innovative system of biotin/avidin ligands on the surface of the reparative cells and multivalent antibody recruitment of cells binding type II collagen. Reparative tissues are analyzed over time by histopathology and gene expression by RT-PCR. We are (3) further optimizing the recruitment and integration of replacement cells in the cartilage lesion by treatment with MabCII-targeted nanosomes loaded with an inhibitor of the activation of the NF-κB pathway to minimize MMP, a known factor in degradation of cartilage matrices. Diminishing MMP production will be a prototypic target for enhancing reparative efforts. The MabCII- targeted nanosomes encapsulating a selective inhibitor of human IKK-2, an activator of the NF-κB pathway, will be used as a local delivery system to reduce MMPs in damaged cartilage lesions prior to treatment with reparative cells enhancing their survival at the degenerative site. !

关节炎是美国残疾的主要原因。既往关节损伤的患者有早期关节炎的风险。 创伤后骨关节炎（PTOA）的发展，即使是重建手术。PTOA可见于 与年龄相关的骨关节炎相比，年轻患者的发病率更高， 物理职业需求（即，军事人员）。目前，PTOA治疗主要用于疼痛， 关节衰竭和关节置换手术，这是一种与长期康复相关的昂贵治疗。的 我研究的总体目标是开发一种有针对性的纳米药物，可以阻止软骨退化， 提高生活质量，减少患者对关节置换的需求。检测早期软骨的能力 创伤性损伤或退行性关节炎的损害有限，在治疗可能的情况下阻碍了治疗 更有益。这些疾病中软骨表面蛋白聚糖/糖蛋白的消耗 导致下面的II型胶原（CII）的暴露。这使得CII可以作为免疫学上的 II型胶原蛋白单克隆抗体（MabCII）的可识别靶点。荧光MabCII可用于 软骨损伤或变性的诊断或与纳米体偶联的MabCII可以靶向包封的药物 用于局部递送到软骨损伤处。我们的初步证据表明，类似的策略可以针对 将修复性软骨细胞或间充质干细胞招募到受损部位。因此，MabCII用于 将修复细胞导向关节软骨和关节软骨损伤的综合治疗计划 并通过创新的荧光关节镜进行监测。此外，招聘和整合 通过减少基质金属蛋白酶（MMP）， 通过关节内注射核活化的药理学抑制剂在关节中产生 因子κ B（NF-κ B）途径包封在MabCII靶向纳米体中。这些程序 对于关节损伤和疾病的诊断和治疗来说，这是一种非常新颖和范式转变。我正在使用 它们的作用是：（1）早期诊断关节面和踝关节的损伤和退行性变 使用灵敏的MabCII抗体引导的荧光关节镜检查方法在猪膝关节软骨中的应用 （FA）。我们的PTOA模型使用了手术诱导的膝关节软骨和关节软骨损伤， 家猪猪膝关节在大小、承重要求和软骨方面与人类关节非常相似 厚使用荧光关节镜检查，通过其与荧光MabCII的结合来观察损伤， 新的程序，我们已经开发，并通过组织病理学证实。FA表征后， 损伤，（2）用MabCII将修复细胞靶向膝盖中受损软骨的区域 抗体的我们正在研究荧光，MabCII靶向软骨细胞或 关节内注射来自骨髓和脂肪组织的间充质干细胞 在关节或踝关节软骨已经手术损伤的情况下，监测细胞定位， 坚持FA。在膝盖软骨损伤处的细胞到细胞的募集通过一种创新的 修复性细胞表面的生物素/抗生物素蛋白配体系统和 结合II型胶原的细胞。通过组织病理学和基因分析， 通过RT-PCR表达。我们正在（3）进一步优化招聘和整合替换 通过用装载有软骨损伤的抑制剂的MabCII靶向纳米体治疗， 激活NF-κB通路以使MMP最小化，MMP是软骨降解的已知因子 矩阵减少MMP的产生将是加强修复努力的一个典型目标。MabCII- 靶向纳米体包封人IKK-2的选择性抑制剂，NF-κB途径的激活剂， 将用作局部递送系统，以在用以下药物治疗之前减少受损软骨病变中的MMP 修复细胞增强其在退行性部位的存活。 !