Glycans in joint disease and glycosylated lubricin mimetics for osteoarthritis therapy

项目总结/摘要 本申请寻求支持专业委员会认证（ACVS）马兽医着手 作为一名临床科学家的独立职业。申请人建议采用多学科方法， 研究关节润滑和骨关节炎（OA），利用软骨润滑方面的领先专家 康奈尔大学的力学、高分子化学和整形外科研究， 斯坦福大学。申请人将在劳伦斯·博纳萨博士和大卫博士的实验室工作 普特南在生物医学工程系，除了她自己的专用实验室空间， 兽医中心和动物研究机构在兽医学院和威尔 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， 在培养研究生和博士后科学家方面成绩卓著。普特南博士是 高分子化学和康奈尔生物材料中心的创始主任。尼克松博士是一名兽医学博士 临床科学家和大型动物整形外科医生，牛仔竞技表演博士是医学博士临床科学家， 整形外科医生尼克松博士和牛仔竞技表演博士都是骨科转化研究的专家， 培养博士后临床科学家的记录，现在在独立的学术教师职位。在 除了这些主要的导师外，申请人还组建了一个由热心合作者组成的团队，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）， 为拟议的研究小组增加广度和深度。康奈尔大学的研究环境是 在生物医学工程，转化骨科研究， 和化学工程，在合成糖生物学方面的合作者Bertozzi博士的专业知识下， 这是拟议研究的重要方面。申请人的提案将询问 在关节疾病中，润滑素的糖基化改变，糖基化在关节疾病的设计和功能中的重要性， 合成的润滑素模拟物，以及糖工程化的润滑素生物模拟物改善糖尿病患者疾病的能力。 OA的啮齿动物膝关节不稳定模型。将采用凝集素印迹法和质谱法来表征 来自Aim 1中的细胞培养上清液和正常和OA关节的聚糖谱。在目标2中， 糖化学技术将用于合成、表征和测试的体外润滑功能 糖工程模拟物。使用由以下提供的化合物合成的糖工程化润滑素模拟物， Drs. Putnam，Bonassar和Bertozzi，申请人将研究糖工程模拟物在细胞内表达的能力。 在目的3中的OA的大鼠前交叉韧带横断模型中预防OA的进展。是 我期望候选人将开始这项研究作为一个初级教员在康奈尔大学 临床科学系，75%的研究承诺和25%的临床服务承诺。

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.