Controlling mechanical signal transduction to treat osteoarthritis

描述(申请人提供)：控制机械信号转导治疗骨关节炎摘要TRPV4钙(钙)离子通道已被证明在软骨细胞中表达并具有功能，软骨细胞负责维持承重关节中的软骨。关节创伤和随后的软骨损伤，以及肥胖症中关节负荷的慢性增加，都是已知的骨关节炎的诱发因素，在美国和许多其他国家，骨关节炎是一种对健康、社会经济具有重大影响的疾病。以前的工作，包括我们自己的工作，明确地将TRPV4与骨性关节炎联系起来。在健康和疾病中，TRPV4似乎是软骨细胞对机械负荷反应的必要和关键调节因子。因此，我们建议使用TRPV4的选择性调节剂来延缓骨关节炎的发展。在这方面，我们已经开发了几个小分子化合物，作为通道的选择性激动剂和拮抗剂。因此，我们实际上有能力开启和关闭通道的活动，提供了一种“调节”软骨细胞对机械负荷的敏感度的方法。在这项合作的小型企业和学术界的努力中，我们将探索这些新化合物在关节损伤的细胞和动物模型中的作用。明确的目标是确定TRPV4调节剂可以有效地调节软骨细胞的信号转导，从而使化合物能够减轻对软骨细胞和软骨的损伤。我们将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效果，其机制是通过暂时调节渗透机械转导，最终导致软骨保护。TRPV4小分子激动剂和拮抗剂的开发对骨关节炎等软骨疾病的治疗具有重要意义。作为学术界和小企业的合作伙伴，我们设想共同开发这些化合物，并将其推向临床试验。除了单一创伤导致的关节损伤外，我们还将肥胖导致的更慢性关节损伤视为一个明确的目标。

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.