Controlling mechanical signal transduction to treat osteoarthritis

摘要TRPV4钙（Ca++）可渗透离子通道已被证明在软骨细胞中表达并起作用，软骨细胞负责维持负重关节的软骨。关节创伤导致的软骨损伤，以及长期增加的关节负荷（如肥胖），是已知的骨关节炎发展的易感因素。在美国和许多其他国家，骨关节炎是一种对健康、社会经济产生重大影响的疾病。之前的工作，包括我们自己的工作，明确地将TRPV4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因子。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，作为通道的选择性激动剂和拮抗剂。因此，我们实际上有能力打开和关闭通道的活动，提供一种“调节”软骨细胞对机械负荷的敏感性的方法。在这个小型企业与学术界合作的项目中，我们将探索这些新化合物在细胞和动物关节损伤模型中的作用。目的是明确确定TRPV4调节剂，可以有效地调节软骨细胞中的信号转导，从而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具有有益的作用，通过渗透机械转导的暂时调节机制，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。作为学术界和小型企业的合作伙伴，我们设想共同开发这些化合物，并将其推向临床试验。除了单一创伤引起的关节损伤外，我们还看到肥胖导致的慢性关节损伤是一个明确的目标。

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.