Controlling mechanical signal transduction to treat osteoarthritis

控制机械信号转导治疗骨关节炎

基本信息

批准号：
8452839
负责人：
WOLFGANG B. LIEDTKE
金额：
$ 29.97万
依托单位：
CYTEX THERAPEUTICS INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8452839
关键词：
Academia Affect Age Age-Years Agonist Animal Model Animals Athletic Injuries Attenuated Biochemical Biomechanics Body Weight Businesses Calcium Cartilage Cartilage Diseases Cartilage injury Cations Cell model Cells Cellular Assay Cellular Mechanotransduction Cellular Stress Charge Chemicals Chondrocytes Chronic Clinical Trials Collaborations Complex Country Degenerative polyarthritis Development Dinoprostone Disease Elderly Elements Equilibrium Etiology Event Extracellular Matrix Family suidae Friction Gait Gene Targeting Goals Health Histopathology Homeostasis Human Genetics Image Impairment Incidence Inflammatory Injury Interleukin-1 Ion Channel Joints Knockout Mice Lead Left Life Link Maintenance Mechanical Stress Mechanics Mediating Metabolic Military Personnel Modification Morphology Mus Obesity Osteoarthrosis Deformans Pain Pathologic Pathology Phase Phenotype Physical environment Physiological Play Population Positioning Attribute Predisposing Factor Prevalence Property Proteoglycan Public Health Publishing Radiology Specialty Reading Regulation Role Signal Transduction Signaling Molecule Stress Surface Testing Therapeutic Time Trauma Traumatic Arthropathy Treatment Efficacy United States Weight-Bearing state Work abstracting aged arthropathies articular cartilage attenuation base cytokine early onset human disease in vivo in vivo Model inhibitor/antagonist insight joint injury joint loading loss of function mouse model novel public health relevance research study response response to injury small molecule socioeconomics

项目摘要

DESCRIPTION (provided by applicant): Controlling mechanical signal transduction to treat osteoarthritis Abstract The TRPV4 calcium (Ca++) permeable ion channel has been shown to be expressed and functional in chondrocytes, the cells responsible for the maintenance of cartilage in weight-bearing joints. Trauma of joints with subsequent damage of cartilage, as well as chronically increased joint load as in obesity, are known predisposing factors for development of osteoarthritis, a disease with major impact - health, socioeconomic - in the US and many other countries. Previous work, including our own, unambiguously links TRPV4 to osteoarthritis. TRPV4 appears to be a necessary and critical regulator of chondrocytes' response to mechanical loading in both health and disease. Thus, we propose to use selective modulators of TRPV4 to attenuate development of osteoarthritis. In this respect, we have developed several small molecule compounds that serve as selective agonists and antagonists of the channel. Therefore we have the ability in effect to turn on and off the activity of the channel, providing a means of "tuning" the chondrocytes' sensitivity to mechanical loading. In this collaborative small business-academia effort we will explore the effects of these novel compounds in cellular and animal models of articular injury. The goal is explicitly to identify TRPV4 modulators that can effectively tune signal transduction in chondrocytes so that the compounds will attenuate injury to chondrocytes and cartilage. We will assess whether these compounds have beneficial effects in an animal model of post-traumatic joint injury by mechanism of a temporary tuning of osmo-mechanotransduction, which ultimately will result in chondroprotection. The development of small molecule agonists and antagonists of TRPV4 has important implications in the treatment of cartilage diseases such as osteoarthritis. As academia- small business collaborators, we envision to develop these compounds jointly and move them forward towards clinical trials. Beyond single-trauma induced joint injury, we also see as a clear target the more chronic joint injury facilitated by obesity.

描述（由申请人提供）：控制机械信号转导以治疗骨关节炎摘要TRPV4钙（Ca ++）可渗透离子通道已被证明是表达并在软骨细胞中功能功能，该细胞是负责体重接缝中软骨的维持的细胞。关节的创伤，随后的软骨损害以及肥胖症的慢性损害以及长期增加的关节负荷是已知的易感性因素，导致了骨关节炎的发展，一种在美国和许多国家中具有重大影响 - 健康，社会经济的疾病。以前的工作，包括我们自己的明确的工作，将TRPV4与骨关节炎联系起来。 TRPV4似乎是软骨细胞对健康和疾病中机械负荷反应的必要和关键调节剂。因此，我们建议使用TRPV4的选择性调节剂来减轻骨关节炎的发展。在这方面，我们开发了几种小分子化合物，它们是该通道的选择性激动剂和拮抗剂。因此，我们有效地打开和关闭通道活动的能力，提供了一种“调整”软骨细胞对机械载荷的敏感性的方法。在这项合作的小型企业 - academia努力中，我们将探讨这些新颖化合物在关节损伤的细胞和动物模型中的影响。该目标是明确识别可以有效调节软骨细胞中信号转导的TRPV4调节剂，以便化合物会减轻对软骨细胞和软骨的损伤。我们将通过暂时调整OSMO-Mechanotransduction的机制来评估这些化合物在创伤后关节损伤的动物模型中是否具有有益的作用，这最终会导致软骨保护。 TRPV4的小分子激动剂和拮抗剂的发展对治疗软骨疾病（如骨关节炎）具有重要意义。作为学术界 - 小型企业合作者，我们设想共同开发这些化合物，并将它们推向临床试验。除了单创伤性诱导的关节损伤之外，我们还将肥胖促进的慢性关节损伤更加明显。