Development of a photoreversible Ca2+ chelator to mimic calcium signaling

描述(由申请人提供)：在理解正常和异常钙信号对其蛋白质靶标的影响方面存在根本差距。这项研究的长期目标是开发可用于阐明正常和异常钙信号在分子水平上的结构和功能后果的化学工具。这项资助申请的总体目标是开发一种新的方法，在体外模拟广泛的生理钙信号模式，并有可能在体内使用。这一应用的中心假设是，已知的对光反应发生可逆结构变化的有机化合物(光致变色化合物)可以用适当的配体进行修饰，以创建一个可逆的钙笼。这项拟议研究的基本原理是，一旦开发出来，这种方法将被用来破译钙信号的影响，最终导致对人类正常和不健康状况的洞察。因此，这项拟议的研究与NIH的任务相关。我们计划测试我们的中心假设，并通过追求以下两个具体目标来实现此应用程序的目标。1)。提高了在生理条件下模拟钙信号的萘并吡喃类螯合剂的金属结合亲和力和钙离子选择性。2)调节可逆光开关的结合特性，以获得更大幅度的振荡钙信号。这个项目是创新的，因为它将创造一种方法学，可以用来研究动态钙信号的影响，而不需要启动整个信号转导级联反应。这项拟议的研究意义重大，因为它有望提供一种化学工具，用于促进对钙信号的理解，并阐明与钙信号相关的某些疾病的分子基础。 与公共健康相关：钙信号控制广泛的重要细胞过程，并与许多疾病有关。有关钙信号和相关疾病的基础知识将使科学家能够开发出维持和改善健康的药剂。

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding the effects of normal and abnormal calcium signals on their protein targets. The long-term goal of this research is to develop chemical tools that may be used to elucidate the molecular-level structural and functional consequences of normal and abnormal calcium signals. The overall objective of this grant application is the development of a novel method to mimic a wide range of physiological calcium signaling patterns in vitro with potential for use in vivo. The central hypothesis of this application is that organic compounds known to undergo reversible structural changes in response to light (photochromic compounds) may be modified with appropriate ligands to create a reversible "cage" for calcium. The rationale for the proposed research is that, once developed, this method will be used to decipher the effects of calcium signals, eventually leading to insights about both normal and unhealthy conditions in humans. Thus, the proposed research is relevant to NIH's mission. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following two Specific Aims. 1). Increase the metal binding affinity and Ca2+ selectivity of the naphthopyran-based chelator for mimicking calcium signals under physiological conditions. 2) Tune the binding properties of the reversible photoswitch to achieve larger amplitude oscillatory calcium signals. This project is innovative because it will create methodology that may be used to investigate the effects of dynamic calcium signaling without initiating an entire signal transduction cascade. The proposed research is significant, because it is expected to contribute a chemical tool that may be used to advance understanding of calcium signaling as well as to elucidate the molecular basis of certain diseases associated with calcium signaling. PUBLIC HEALTH RELEVANCE: Calcium signals control a wide range of important cellular processes, and are associated with many diseases. Fundamental knowledge about calcium signaling and related diseases will enable scientists to develop pharmaceutical agents that to maintain and improve health.