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：
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
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/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

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）：粘多糖糖（MPS）是遗传的，是由于糖胺糖（GAG）降解所需的特定溶酶体酶的不足而导致的结缔组织疾病。在所涉及的各种器官系统中，骨骼和关节受到严重影响。尽管目前已经或正在为MPS患者评估了几种疗法，但对骨骼和关节的积极影响受到限制。此外，没有适当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储存激活了类似Toll的受体-4（TLR4）信号传导途径，从而导致炎症，凋亡和细胞增殖的复杂模式。反过来，这会导致异常结缔组织基质稳态，从而导致骨骼和关节破坏。该项目使用MPS型VI的大鼠和CAT模型提出了三个具体目标。 AIM 1将进一步研究通过a）使用Toll样受体4（TLR4）记者细胞系和敲除小鼠来评估GAG对TLR4激活的直接影响，b）使用TLR4激活的直接影响，b）连续量化产物和培养基介质的MOR介导，以评估GAG对TLR4激活的直接影响，以评估GAG的直接影响，并在MPS结缔组织中进一步研究MPS结缔组织的信号传导异常。 c）检查导致两种重要信号脂质脂质脂质的机制，神经酰胺和鞘氨氨酸1-磷酸（S1P）。 AIM 2将通过a）通过a）从各个疾病严重程度的各个阶段的MPS VI猫获得这些材料来探索血浆和滑膜作为生物标志物的来源，并将几种促炎/促凋亡蛋白和脂质蛋白和脂质蛋白和脂质（ceramide and s1p）与年龄匹配的猫的水平进行比较。研究者还将比较血浆和滑液中的GAG水平从MPS VI CAT中与尿液中发现的那些，b）使用MPS VI CAT滑液进行蛋白质组学分析，旨在识别该疾病中异常表达的新型蛋白质，并通过从血浆和vi中进行了c），并在人体MPS中进行了治疗，c）以前是c）。治疗，并评估从上面概述的动物实验中鉴定出的几种生物标志物的表达。根据初步发现，AIM 3将评估MPS VI大鼠中TNF-A抑制剂和抗凋亡药物的功效。要研究的四个分子中的每一个都已经显示出在关节炎的动物模型中的功效，一个（Remicade（TM））在临床上可用。项目叙述：国会议员疾病是毁灭性的，通常是致命的疾病。作为一个小组，据估计，它们的发生率可能高达1：10,000，在某些人群中可能会更高。这些疾病的当前治疗策略非常昂贵，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轻国会议员及其居住社会的疾病和经济负担。这是拟议研究的长期目标