Notochordal Cell Derived Therapies for Painful Disc Degeneration

 描述(申请人提供)：腰椎间盘(IVD)退行性变是一种衰弱的疾病，与腰痛的发病机制有关，相关成本每年可超过1000亿美元。Parent奖的总体目标是开发以微创方式使用的新型治疗剂和策略，以限制退变，恢复IVD结构，并减少退行性间盘疾病的痛苦状况。我们第一年的父母拨款的初步数据强调了蛋白多糖结构和硫酸盐化模式在抑制神经血管侵入IVD的线索中至关重要的作用。与蛋白多糖在IVD基质中的重要性一样，多年来在糖胺多聚糖(GAG)结构和硫化模式的表征方面一直没有重大进展。这项BIRT将新技术引入IVD研究领域，允许对蛋白多糖进行表征，而不仅仅是GAG含量测量，以包括发挥重要生物活性作用的特征。BIRT计划发展了西奈山的James Iatridis博士和伦斯勒理工学院的Robert Linhardt博士之间的新合作。我们将IVD研究方面的专业知识与一位蛋白多糖专家相结合，以开发和应用新技术来表征和分离IVD中的GAG。我们认为，仅通过蛋白多糖的糖胺聚糖(GAG)含量来表征蛋白多糖，会减缓IVD和软骨的研究。蛋白多糖的结构或硫酸盐化模式与许多重要的生物活性作用有关，包括神经血管的生长。目的1是利用人体尸检样本和腰椎间盘摘除手术中疼痛的IVD手术样本，表征人类IVD的GAG谱随IVD区域的增长、老化和疾病。目的2利用细胞培养模型研究从人静脉畸形中分离的不同GAG结构(CS4、CS6、KS和DS)对神经血管生长的影响。这个项目意义重大，因为软骨组织中的GAG结构和硫酸盐化模式没有得到充分的研究，而这些概念与间盘源性背痛问题高度相关。这种方法是创新的，因为它包括了先进的血糖测量。传播里程碑包括向RPI和西奈山的研究生教授这些新技术，并在一次国际研究会议上向IVD研究人员介绍这些技术和新科学。

 DESCRIPTION (provided by applicant): Intervertebral disc (IVD) degeneration is a debilitating disorder implicated in the pathogenesis of low back pain with associated costs that can exceed $100 billion annually. The overall goal of the parent award is to develop novel therapeutic agents and strategies for use in a minimally invasive manner to limit degeneration, restore IVD structure, and reduce painful conditions of degenerative disc disease. Our year 1 preliminary data of the parent grant highlight the crucially important role of proteoglycan structure and sulfation pattern in cues to inhibit neurovascular invasion into the IVD. As important as proteoglycans are in the IVD matrix, there has not been a major advance in the characterization of glycosaminoglycan (GAG) structure and sulfation patterns in many years. This BIRT introduces new technologies to the IVD research field that allow characterization of proteoglycans, beyond GAG content measurements, to include features that play important bioactive roles. This BIRT proposal develops a new collaboration between Dr. James Iatridis at Mount Sinai and Dr. Robert Linhardt at Rensselaer Polytechnic Institute. We combine expertise in IVD research with a proteoglycan expert in order to develop and apply novel techniques for the characterization and isolation of GAGs in the IVD. We believe that IVD and cartilage research is slowed by the characterization of proteoglycans by their glycosaminoglycan (GAG) content alone. The structure or sulfation patterns of proteoglycans are responsible for many important bioactive roles including neurovascular growth. Aim 1 is to characterize the GAG profile of human IVDs with growth, aging and disease across IVD regions using human autopsy samples and surgical samples from painful IVDs during discectomy surgery. Aim 2 is to characterize the effects of different GAG structures (CS4, CS6, KS& DS) that are isolated from human IVDs on neurovascular growth using cell culture models. This project is significant because the GAG structure and sulfation patterns are underexplored in cartilaginous tissues and these concepts are highly relevant to the problem of discogenic back pain. The approach is innovative because it includes advanced glycomics measurements. Dissemination milestones involve teaching these novel technologies to graduate students at both RPI and Mount Sinai and also introducing these techniques and new science to IVD researchers at an international research meeting.