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：
8460499
负责人：
CALOGERA Maria SIMONARO
金额：
$ 34.87万
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/8460499
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 Bone Diseases 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 I S Mucopolysaccharidosis VI Mucopolysaccharidosis VII Mus Patients Pattern Pharmaceutical Preparations Pilot Projects Plasma Population Proteins Proteomics Public Health Rattus Recombinants Reporter Research Role Severity of illness Signal Pathway Signal Transduction Signaling Molecule Societies Source Sphingolipids Sphingomyelinase Staging Synovial Cell Synovial Fluid Synovial Membrane TNF gene TNFSF11 gene Therapeutic Therapeutic Studies Urine Western Blotting arthropathies base body system bone burden of illness 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

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: We 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 pro- inflammatory 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: We 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. We 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. Aim 3: Based on our preliminary findings, we will evaluate the efficacy of TNF-¿ 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") is clinically available.

粘多糖贮积症 (MPS) 是一种遗传性结缔组织疾病，由缺乏粘多糖引起糖胺聚糖 (GAG) 降解所需的特定溶酶体酶的活性。尽管有多种治疗方法，但骨骼和关节受到严重影响。已经或正在对 MPS 患者进行评估，对骨骼和关节的积极影响已被证实此外，没有合适的生物标志物可用于监测这些药物的有效性。这项研究的基本假设是 GAG 储存在 MPS 中。个体激活 Toll 样受体 4 (TLR4) 信号通路，导致复杂的模式炎症、细胞凋亡和细胞增殖反过来会导致结缔组织基质异常。体内平衡，导致骨骼和关节破坏，该项目提出了三个具体目标。 MPS VI 型大鼠和猫模型目标 1：我们将进一步研究 GAG 诱导的机制。 MPS 结缔组织中的信号传导异常，通过 a) 使用 Toll 样受体 4 (TLR4) 报告细胞系和敲除小鼠评估 GAG 对 TLR4 激活的直接影响，b) 继续量化 pro- MPS 软骨细胞和滑膜细胞提取物和培养基中的炎症和促凋亡蛋白，以及 c) 检查导致 GAG 介导的两种重要信号脂质神经酰胺异常的机制目标 2：我们将探索使用血浆和滑液作为来源。 MPS 疾病的生物标志物，方法是：a) 从不同阶段的 MPS VI 猫中获取这些材料疾病严重程度，并比较几种促炎/促凋亡蛋白和脂质的水平（神经酰胺和 S1P）与年龄匹配的正常猫中的 GAG 水平进行比较。 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) 通过关节内注射从人类 MPS VI 患者治疗前后获取血浆和滑液酶替代疗法，并评估从动物中鉴定出的几种生物标志物的表达目标 3：根据我们的初步发现，我们将评估 TNF-¿ 的功效。抑制剂和抗细胞凋亡药物已在 MPS VI 大鼠中得到研究。在关节炎动物模型中显示出疗效，其中一种（Remicade）已投入临床使用。