Controlling mechanical signal transduction to treat osteoarthritis

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TRPV 4钙（Ca++）渗透性离子通道已被证明在软骨细胞中表达和起作用，软骨细胞负责维持承重关节中的软骨。关节创伤伴随软骨的后续损伤，以及慢性增加的关节负荷（如肥胖症）是骨关节炎发展的已知诱发因素，骨关节炎是一种在美国和许多其他国家对健康、社会经济产生重大影响的疾病。以前的工作，包括我们自己的工作，明确地将TRPV 4与骨关节炎联系起来。TRPV4似乎是健康和疾病中软骨细胞对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，我们已经开发了几种小分子化合物，作为选择性激动剂和拮抗剂的通道。因此，我们有能力有效地打开和关闭通道的活动，提供了一种“调节”软骨细胞对机械负荷的敏感性的方法。在这个合作的小企业，学术界的努力，我们将探讨这些新的化合物在关节损伤的细胞和动物模型的影响。目标明确地是鉴定TRPV4调节剂，其可以有效地调节软骨细胞中的信号转导，使得化合物将减轻对软骨细胞和软骨的损伤。我们将评估这些化合物是否在创伤后关节损伤的动物模型中通过暂时调节软骨机械转导的机制具有有益作用，这最终将导致软骨保护。TRPV4的小分子激动剂和拮抗剂的开发在软骨疾病如骨关节炎的治疗中具有重要意义。作为学术界和小企业的合作者，我们设想共同开发这些化合物，并将其推向临床试验。除了单一创伤引起的关节损伤，我们还将肥胖促进的慢性关节损伤视为明确的目标。

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.