Glycans in joint disease and glycosylated lubricin mimetics for osteoarthritis therapy

关节疾病中的聚糖和用于骨关节炎治疗的糖基化润滑素模拟物

• 批准号: 10207469
• 负责人: Heidi Reesink
• 金额: $ 20.44万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207469
• 关键词: Adhesives; Adsorption; Affect; Affinity; Aging; Animals; Anterior Cruciate Ligament; Attenuated; Binding; Biochemical; Biocompatible Materials; Biological Assay; Biology; Biomechanics; Biomedical Engineering; Biomimetics; Biophysics; Cartilage; Cell Culture Techniques; Chemical Engineering; Chemicals; Chondrocytes; Clinical; Clinical Sciences; Clinical Services; Coculture Techniques; Custom; Data; Degenerative polyarthritis; Development; Dimensions; Discipline; Disease; Environment; Equus caballus; Experimental Arthritis; Faculty; Fracture; Friction; Galactosides; Galectin 3; Gene Expression; Glycobiology; Glycoconjugates; Glycoproteins; Histologic; Human; Impairment; In Vitro; Inflammation; Inflammatory; Injections; Joints; Knee; Knowledge; Laboratories; Laboratory Animal Production and Facilities; Lectin; Link; Lubricants; Lubrication; MALDI-TOF Mass Spectrometry; Mass Spectrum Analysis; Measures; Mechanics; Medical center; Mentors; Methods; Microscopy; Modeling; Motion; Mucinous; Mucins; Orthopedics; Pain; Polymer Chemistry; Polysaccharides; Positioning Attribute; Postdoctoral Fellow; Property; Proteoglycan; Publishing; Rattus; Recombinants; Records; Research; Rheumatoid Arthritis; Rodent; Rodent Model; Role; Scientist; Specialty Boards; Spectrometry, Mass, Electrospray Ionization; Supplementation; Surface Plasmon Resonance; Surgeon; Synovial Fluid; Techniques; Testing; Training; Translational Research; Trauma; Traumatic injury; Universities; Veterinarians; Veterinary Medicine; Work; anterior cruciate ligament injury; arthropathies; articular cartilage; base; biophysical properties; carbohydrate structure; career; clinically relevant; college; crosslink; cytokine; design; gene therapy; glycosylation; graduate student; in vivo; indexing; interdisciplinary approach; joint function; joint inflammation; joint injury; lubricin; medical schools; member; mimetics; post-doctoral training; preservation; prevent

Project Summary/Abstract This application seeks support for a specialty board certified (ACVS) equine veterinarian embarking upon an independent career as a translational clinical scientist. The applicant proposes a multi-disciplinary approach to study joint lubrication and osteoarthritis (OA), taking advantage of leading experts in cartilage lubrication mechanics, polymer chemistry and orthopedic research at Cornell University and synthetic glycobiology at Stanford University. The applicant would work in the laboratories of Dr. Lawrence Bonassar and David Putnam in the Department of Biomedical Engineering, in addition to her own dedicated laboratory space in the Veterinary Medical Center and animal research facilities at the College of Veterinary Medicine and Weill Medical College. Dr. Bonassar has published extensively on lubricin and cartilage biomechanics and also has an outstanding record of training graduate students and post-doctoral scientists. Dr. Putnam is an expert in polymer chemistry and the Founding Director of the Cornell Center for Biomaterials. Dr. Nixon is a DVM clinician scientist and large animal orthopedic surgeon, and Dr. Rodeo is an MD clinician scientist and orthopedic surgeon. Both Drs. Nixon and Rodeo are experts in orthopedic translational research with proven track records for training post-doctoral clinician scientists now in independent academic faculty positions. In addition to these primary mentors, the applicant has assembled a team of enthusiastic collaborators, including experts in advanced microscopy (Dr. Matthew Paszek) and synthetic glycobiology (Dr. Carolyn Bertozzi), who add both breadth and depth to the proposed research team. The research environment at Cornell is exceptionally strong in the relevant disciplines of biomedical engineering, translational orthopedic research, and chemical engineering, with the expertise of collaborator Dr. Bertozzi in synthetic glycobiology adding a significant dimension to the proposed research. The applicant's proposal would interrogate how the glycosylation of lubricin is altered in joint disease, the importance of glycosylation in the design and function of synthetic lubricin mimetics, and the ability of glycoengineered lubricin biomimetics to ameliorate disease in a rodent knee instability model of OA. Lectin blotting and mass spectrometry will be employed to characterize glycan profiles from both cell culture supernatants and normal and OA joints in Aim 1. In Aim 2, synthetic glycochemistry techniques will be utilized to synthesize, characterize and test the in vitro lubricating function of glycoengineered mimetics. Using glycoengineered lubricin mimetics synthesized from compounds provided by Drs. Putnam, Bonassar and Bertozzi, the applicant will investigate the ability of glycoengineered mimetics to prevent the progression of OA in the rat anterior cruciate ligament transection model of OA in Aim 3. It is expected that the candidate will begin this research as a junior faculty member in the Cornell University Department of Clinical Sciences with an 75% research commitment and 25% clinical service commitment.

项目摘要/摘要 此应用程序寻求支持专业委员会认证(ACVS)的马匹兽医开始 作为一名翻译临床科学家的独立职业。申请人提出了一种多学科的方法来 研究关节润滑和骨关节炎(OA)，利用领先的软骨润滑专家 康奈尔大学的力学、聚合物化学和整形外科研究以及合成糖生物学 斯坦福大学。申请者将在劳伦斯·博纳萨博士和大卫的实验室工作 Putnam在生物医学工程系，除了她自己在 威尔兽医学院兽医中心和动物研究设施 医学院。Bonassar博士在润滑素和软骨生物力学方面发表了大量文章，还 培养研究生和博士后科学家成绩突出。帕特南博士是一位 聚合物化学和康奈尔生物材料中心的创始主任。尼克松博士是个DVM 临床科学家和大型动物整形外科医生，Rodeo博士是MD临床科学家和 整形外科医生。尼克松博士和罗迪奥博士都是矫形外科翻译研究方面的专家， 培养目前担任独立学术教职的博士后临床医生科学家的记录。在……里面 除了这些主要导师外，申请人还组建了一支热情的合作者团队，包括 高级显微镜专家(Matthew Paszek博士)和合成糖生物学专家(Carolyn Bertozzi博士)， 为拟议的研究团队增加广度和深度。康奈尔大学的研究环境是 在生物医学工程、翻译性整形外科研究等相关学科中表现异常出色， 和化学工程，与合作者Bertozzi博士在合成糖生物学方面的专业知识增加了一个 这是拟议研究的一个重要方面。申请者的提议将询问如何 关节疾病中润滑素的糖基化改变，糖基化在关节的设计和功能中的重要性 合成润滑素模拟物，以及糖工程润滑剂仿生物改善小鼠疾病的能力 骨关节炎大鼠膝关节不稳定模型的建立。凝集素印迹和质谱学将用于表征 在目标1中，细胞培养上清液以及正常关节和骨关节炎关节中的多糖图谱。在目标2中，合成 将利用糖化学技术来合成、表征和测试体外润滑功能 糖工程模拟物。使用由以下提供的化合物合成的糖工程润滑剂模拟物 Putnam，Bonassar和Bertozzi博士，申请者将研究糖工程模拟物的能力 目的3预防大鼠前交叉韧带切断后骨性关节炎的进展。 预计候选人将以康奈尔大学初级教员的身份开始这项研究 临床科学系，75%的研究承诺和25%的临床服务承诺。

项目成果

Lubricin in experimental and naturally occurring osteoarthritis: a systematic review.

• DOI: 10.1016/j.joca.2020.05.009
• 发表时间: 2020-10
• 期刊: Osteoarthritis and cartilage
• 影响因子: 7
• 作者: Watkins AR;Reesink HL
• 通讯作者: Reesink HL

Assessment of osteoarthritis functional outcomes and intra-articular injection volume in the rat anterior cruciate ligament transection model.

• DOI: 10.1002/jor.25245
• 发表时间: 2022-09
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Wang, Yuyan;Wagner, Emma S.;Yu, Danqiao;Chen, Kevin J.;Keel, Taidhgin J.;Pownder, Sarah L.;Koff, Matthew F.;Cheetham, Jonathan;Samaroo, Kirk J.;Reesink, Heidi L.
• 通讯作者: Reesink, Heidi L.

Synovial fluid lubricin increases in spontaneous canine cruciate ligament rupture.

• DOI: 10.1038/s41598-020-73270-2
• 发表时间: 2020-10-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Wang Y;Gludish DW;Hayashi K;Todhunter RJ;Krotscheck U;Johnson PJ;Cummings BP;Su J;Reesink HL
• 通讯作者: Reesink HL

Selective and Tunable Galectin Binding of Glycopolymers Synthesized by a Generalizable Conjugation Method.

• DOI: 10.1021/acs.biomac.9b00759
• 发表时间: 2019-10-14
• 期刊: Biomacromolecules
• 影响因子: 6.2
• 作者: Zhou C;Reesink HL;Putnam DA
• 通讯作者: Putnam DA