Novel Therapies and Biomarkers for the Mucopolysaccharidoses

粘多糖症的新疗法和生物标志物

• 批准号: 7727608
• 负责人: CALOGERA Maria SIMONARO
• 金额: $ 40.68万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/7727608
• 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

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（由申请方提供）：粘多糖沉积症（MPS）是一种遗传性结缔组织疾病，由糖胺聚糖（GAG）降解所需的特异性溶酶体酶活性不足引起。 在涉及的各种器官系统中，骨骼和关节受到严重影响。 虽然已经或目前正在评估MPS患者的几种治疗方法，但对骨骼和关节的积极影响有限。 此外，没有适当的生物标志物可用于监测这些治疗对骨骼和关节的有效性。 本研究的基本假设是MPS个体中的GAG储存激活Toll样受体-4（TLR 4）信号通路，导致炎症、凋亡和细胞增殖的复杂模式。 这反过来又导致异常的结缔组织基质稳态，导致骨和关节破坏。 本项目使用MPS VI型大鼠和猫模型提出了三个具体目标。 目的1将通过a）使用Toll样受体4（TLR 4）报告细胞系和敲除小鼠来评估GAG对TLR 4活化的直接作用，B）继续定量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，和c）检查导致两种重要信号脂质神经酰胺和鞘氨醇-1-磷酸（S1 P）中GAG介导的异常的机制。 目的2将通过以下方式探索血浆和滑液作为MPS疾病生物标志物来源的用途：a）从疾病严重程度不同阶段的MPS VI猫中获得这些材料，并将几种促炎/促凋亡蛋白和脂质（神经酰胺和S1 P）的水平与年龄匹配的正常猫中发现的水平进行比较。 研究者还将比较MPS VI猫的血浆和滑液中的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，旨在鉴定在该疾病中异常表达的新蛋白质，以及c）在关节内酶替代疗法治疗前后从人MPS VI患者获得血浆和滑液，以及评价从上述动物实验中鉴定的几种生物标志物的表达。 基于初步发现，目标3将评估TNF-α抑制剂和抗凋亡药物在MPS VI大鼠中的功效。 待研究的四种分子中的每一种都已经在关节炎的动物模型中显示出疗效，并且其中一种（Remicade（tm））在临床上可用。 项目叙述：MPS疾病是毁灭性的，往往是致命的疾病。 作为一个群体，据估计，其发生率可能高达1：10，000的出生率，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影响有限。 因此，显然需要新的方法来减少MPS患者及其生活的社会的疾病和经济负担。 这是拟议研究的长期目标