Novel Therapies and Biomarkers for the Mucopolysaccharidoses

粘多糖症的新疗法和生物标志物

基本信息

批准号：
7878699
负责人：
CALOGERA Maria SIMONARO
金额：
$ 40.27万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7878699
关键词：
Affect Aftercare Age Animal Experiments Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptosis Inhibitor Apoptotic Arthritis Arylsulfatase B Biological Markers Birth Breeding Cartilage Caspase Inhibitor Cell Extracts Cell Line Cell Proliferation Ceramidase Ceramides Chondrocytes Collagen Type X Complex Connective Tissue Connective Tissue Diseases Disease Disease Progression Economic Burden Effectiveness Enzymes Felis catus Fibroblasts Gene Expression Glycosaminoglycan Degradation Pathway Glycosaminoglycans Goals Growth Homeostasis Human Hypertrophy In Vitro Inborn Genetic Diseases Incidence Individual Inflammation Inflammatory Inherited Interleukin-6 Intra-Articular Injections Joints Knockout Mice Lead Life Lipids Matrix Metalloproteinases Mediating Metabolism Modeling Molecular Sequence Alteration Monitor Mucopolysaccharidoses Mucopolysaccharidosis VI Mucopolysaccharidosis VII Mus Patients Pattern Pharmaceutical Preparations Pilot Projects Plasma Population Proteins Proteomics Public Health Rattus Recombinants Reporter Research Research Personnel Role Severity of illness Signal Pathway Signal Transduction Signaling Molecule Societies Source Sphingolipids Sphingomyelinase Staging Synovial Cell Synovial Fluid Synovial Membrane TNFSF11 gene Therapeutic Therapeutic Studies Urine Western Blotting arthropathies base body system bone connective tissue metabolism enzyme replacement therapy galactosylgalactosylglucosylceramidase improved in vivo infliximab inhibitor/antagonist joint destruction novel novel marker novel strategies novel therapeutic intervention novel therapeutics pro-apoptotic protein protective effect response sphingosine 1-phosphate sphingosine kinase toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): The mucopolysaccharidoses (MPS) are inherited, connective tissue disorders that result from the deficient activities of specific lysosomal enzymes required for glycosaminoglycan (GAG) degradation. Among the various organ systems involved, the bones and joints are severely affected. Although several therapies have been or are currently being evaluated for MPS patients, the positive effects on bones and joints have been limited. In addition, there are no appropriate biomarkers that can be used to monitor the effectiveness of these therapies for bones and joints. The underlying hypothesis of this research is that GAG storage in MPS individuals activates Toll-like receptor-4 (TLR4) signaling pathways, leading to a complex pattern of inflammation, apoptosis, and cell proliferation. This, in turn, causes abnormal connective tissue matrix homeostasis, resulting in bone and joint destruction. Three specific aims are proposed in this project using the rat and cat models of MPS Type VI. Aim 1 will further examine the mechanisms underlying GAG-induced signaling abnormalities in MPS connective tissues by a) using Toll-like receptor 4 (TLR4) reporter cell lines and knock-out mice to evaluate the direct effects of GAGs on TLR4 activation, b) continuing to quantify proinflammatory and pro-apoptotic proteins in MPS chondrocyte and synovial cell extracts and media, and c) examining the mechanisms leading to GAG-mediated abnormalities in two important signaling lipids, ceramide and sphingosine-1-phosphate (S1P). Aim 2 will explore the use of plasma and synovial fluid as sources of biomarkers for the MPS disorders by a) obtaining these materials from MPS VI cats of various stages of disease severity, and comparing the levels of several pro-inflammatory/pro-apoptotic proteins and lipids (ceramide and S1P) to those found in age-matched normal cats. The investigators will also compare GAG levels in plasma and synovial fluid from the MPS VI cats to those found in urine, b) using the MPS VI cat synovial fluid for a proteomics analysis aimed at identifying novel proteins that are abnormally expressed in this disease, and c) obtaining plasma and synovial fluid from human MPS VI patients before and after treatment by intra-articular enzyme replacement therapy, and evaluating the expression of several biomarkers identified from the animal experiments outlined above. Based on preliminary findings, Aim 3 will evaluate the efficacy of TNF-a inhibitors and anti-apoptotic drugs in the MPS VI rats. Each of the four molecules to be studied has already shown efficacy in animal models of arthritis, and one (Remicade(tm)) is clinically available. PROJECT NARRATIVE: The MPS disorders are devastating and often fatal diseases. As a group, it is estimated that they may occur with an incidence as high as 1:10,000 births, and perhaps higher in certain populations. Current therapeutic strategies for these diseases are exceedingly expensive, and have had limited effects in the bones and joints. Thus, new approaches are clearly needed to reduce the disease and economic burden to MPS patients and the societies in which they live. This is the long-term goal of the proposed research

描述（由申请人提供）：粘多糖贮积症（MPS）是遗传性结缔组织疾病，由糖胺聚糖（GAG）降解所需的特定溶酶体酶活性缺陷引起。在涉及的各个器官系统中，骨骼和关节受到严重影响。尽管已经或正在对 MPS 患者的几种疗法进行评估，但对骨骼和关节的积极作用有限。此外，没有合适的生物标志物可用于监测这些疗法对骨骼和关节的有效性。这项研究的基本假设是，MPS 个体中的 GAG 储存会激活 Toll 样受体 4 (TLR4) 信号通路，导致炎症、细胞凋亡和细胞增殖的复杂模式。这反过来会导致结缔组织基质稳态异常，导致骨和关节破坏。该项目使用 MPS VI 型大鼠和猫模型提出了三个具体目标。目标 1 将进一步研究 MPS 结缔组织中 GAG 诱导的信号异常的机制，方法是：a) 使用 Toll 样受体 4 (TLR4) 报告细胞系和基因敲除小鼠来评估 GAG 对 TLR4 激活的直接影响，b)继续量化 MPS 软骨细胞和滑膜细胞提取物和培养基中的促炎和促凋亡蛋白，以及 c) 检查导致两种重要信号脂质中 GAG 介导的异常的机制，神经酰胺和 1-磷酸鞘氨醇 (S1P)。目标 2 将探索血浆和滑液作为 MPS 疾病生物标志物来源的用途，方法是：a) 从疾病严重程度不同阶段的 MPS VI 猫获取这些材料，并比较几种促炎/促凋亡蛋白的水平和脂质（神经酰胺和 S1P）与年龄匹配的正常猫中发现的脂质（神经酰胺和 S1P）相同。研究人员还将比较 MPS VI 猫血浆和滑液中的 GAG 水平与尿液中的 GAG 水平，b) 使用 MPS VI 猫滑液进行蛋白质组学分析，旨在识别在这种疾病中异常表达的新蛋白质，以及c)在通过关节内酶替代疗法治疗之前和之后从人类MPS VI患者获取血浆和滑液，并评估从上述动物实验中鉴定的几种生物标志物的表达。根据初步研究结果，Aim 3将评估TNF-a抑制剂和抗凋亡药物在MPS VI大鼠中的疗效。待研究的四种分子中的每一种都已在关节炎动物模型中显示出功效，其中一种（Remicade(tm)）已投入临床使用。项目叙述：MPS 疾病是毁灭性的且常常是致命的疾病。作为一个群体，估计其发生率可能高达 1:10,000 出生，并且在某些人群中可能更高。目前针对这些疾病的治疗策略非常昂贵，并且对骨骼和关节的效果有限。因此，显然需要新的方法来减少 MPS 患者及其所生活的社会的疾病和经济负担。这是拟议研究的长期目标