CK2.1, a novel peptide for cartilage repair

CK2.1，一种用于软骨修复的新型肽

基本信息

批准号：
10053849
负责人：
ANJA G NOHE
金额：
$ 20.76万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053849
关键词：
Acute Adult Affect Age Aging American Animal Model Apoptosis Architecture Arthritis Automobile Driving Behavior Bone Density Bone Development C57BL/6 Mouse Cartilage Cartilage Matrix Cells Centers for Disease Control and Prevention (U.S.)Chondrocytes Chondrogenesis Clinical Research Collagen Type II Collagen Type X Data Degenerative polyarthritis Development Diagnosis Diffuse Disease Enzymes Exposure to Extracellular Matrix Friction Gait Generations Goals Hand Health Expenditures Hip region structure Human Hydrogels Hypertrophy Impairment Inflammation Injectable Injections Joints Knee Lead Measures Medial meniscus structure Meniscus structure of joint Modeling Mus Natural regeneration Operative Surgical Procedures Osteoblasts Osteocalcin Osteogenesis Pathway interactions Patients Peptide Hydrolases Peptide Signal Sequences Peptides Phenotype Phosphorylation Site Physicians Pilot Projects Play Population Process Production Property Proteins Publishing Quality of life RNA Recombinants Reporting Risk Factors Signal Pathway Signal Transduction Structure Synovial Membrane System Testing Therapeutic Time Tissues Vertebral column bone morphogenetic protein 2 bone morphogenetic protein receptors cartilage repair casein kinase II cell type design foot high reward high risk homeodomain improved joint destruction joint function knee replacement arthroplasty laser capture microdissection mouse model novel novel therapeutics pain symptom particle peptidomimetics prevent receptor repaired tissue repair transcriptome sequencing type IA bone morphogenetic protein receptor uptake

项目摘要

OA is a major debilitating disease caused by the gradual loss of cartilage, primarily affecting the knees, hips, hands, feet, and spine. OA increases aggregate health care expenditures by $186 billion annually. The Centers for Disease Control and Prevention (CDC) estimates 27 million Americans suffer from OA. Estimates show that by year 2030, 20% of the adult U.S. population, or nearly 67 million people, will have physician-diagnosed arthritis. OA treatments focus on reducing inflammation and pain symptoms while joint degradation continues. The lack of repair mechanism will eventually lead to a condition that necessitates total knee replacement surgery. One of the major drawbacks of current therapeutics being developed is the potential to induce chondrocyte hypertrophy. Chondrocytes in OA cartilage show an aberrant hypertrophic phenotype and actively produce cartilage-degrading enzymes. Unfortunately, new treatments in development, such as recombinant BMP2, induce chondrocyte hypertrophy, further exasperating the problem. Therefore, although they are very potent in inducing ECM secretion and stimulating chondrogenesis, they are not useful for OA treatment. We propose the use of novel peptide CK2.1 to treat OA. CK2.1 is a mimetic peptide of the Bone Morphogenetic Protein receptor (BMPRIa). The peptide incorporates the phosphorylation site for Casein Kinase II (CK2) of the BMPRIa (SYED, AA475–479) and contains the Antennapedia Homeodomain signal sequence for cellular uptake. In our pilot study, we demonstrated that CK2.1 has the potential to induce ECM secretion and chondrogenesis without the induction of hypertrophy. We also demonstrated that CK2.1 repaired the cartilage in a DMM mouse model. We further conjugated CK2.1 to hydrogel particles to enable a sustained release of CK2.1 into the intra articular cavity releasing the peptide for multiple days. While results from our pilot study are promising, it is unclear if our novel peptide will induce chondrocyte hypertrophy in the long- term. Furthermore, it is unclear which cell population the peptide acts on, how far it diffuses into the cartilage, and what signaling pathways it activates. This proposal will answer these critical questions that must be answered before CK2.1 can be further developed. This proposal is high risk and also high reward. CK2.1 may be the first peptide that can regenerate cartilage without driving chondrocytes into apoptosis or osteoblasts. If this is the case our studies will revolutionize the clinical research.

OA 是一种由软骨逐渐丧失引起的严重衰弱性疾病，主要影响膝盖、臀部、手、脚和脊柱的 OA 使医疗保健总支出增加 186 美元。疾病控制和预防中心 (CDC) 估计每年有 2700 万。据估计，到 2030 年，20% 的美国成年人患有 OA。或近 6700 万人将接受医生诊断的关节炎治疗。减少炎症和疼痛症状，同时关节退化仍在继续。这种机制最终会导致需要进行全膝关节置换手术的情况。目前正在开发的治疗方法的主要缺点之一是有可能诱发 OA软骨中的软骨细胞肥大。不幸的是，新的治疗方法正在改变表型并积极产生软骨降解酶。重组 BMP2 等开发，会诱导软骨细胞肥大，进一步加剧因此，尽管它们在诱导 ECM 分泌和刺激方面非常有效。软骨形成，它们对于 OA 治疗没有用处。我们建议使用新型肽 CK2.1 来治疗 OA。CK2.1 是一种骨模拟肽。该肽包含形态发生蛋白受体 (BMPRIa) 的磷酸化位点。 BMPRIa (SYED, AA475–479) 的酪蛋白激酶 II (CK2) 并包含触角足在我们的初步研究中，我们证明了 CK2.1 的细胞摄取同源结构域信号序列。具有诱导 ECM 分泌和软骨形成的潜力，而无需诱导我们还证明 CK2.1 可修复 DMM 小鼠模型中的软骨。我们进一步将 CK2.1 与水凝胶颗粒结合，使 CK2.1 能够持续释放到我们的初步研究结果显示，关节腔内释放肽长达数天。是有希望的，目前还不清楚我们的新肽是否会在长期内诱导软骨细胞肥大此外，尚不清楚该肽作用于哪个细胞群，以及它扩散到多远。该提案将回答这些关键问题。在进一步开发 CK2.1 之前必须回答的问题这个提议很高。 CK2.1可能是第一个无需人工再生软骨的肽。如果是这样的话，我们的研究将发生革命性的变化。临床研究。