Development of a photoreversible Ca2+ chelator to mimic calcium signaling

开发光可逆 Ca2 螯合剂来模拟钙信号传导

• 批准号: 8447433
• 负责人: ALISON MCCURDY
• 金额: $ 10.35万
• 依托单位: CALIFORNIA STATE UNIVERSITY LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447433
• 关键词: Affinity; Applications Grants; Award; Binding; Calcium; Calcium Signaling; Cations; Cell physiology; Cells; Chelating Agents; Chemicals; Collaborations; Complex; Data; Defect; Development; Disease; Educational workshop; Environment; Event; Faculty; Fertilization; Fostering; Frequencies; Funding; Future; Gene Activation; Generations; Goals; Grant Review; Health; Human; In Vitro; Individual; Investigation; Ions; Knowledge; Laboratories; Lead; Life; Ligands; Light; Location; Measures; Metals; Methodology; Methods; Mission; Modeling; Molecular; Nature; Organic Synthesis; Outcome; Pattern; Peer Review; Pharmacologic Substance; Photochemistry; Physiological; Positioning Attribute; Process; Productivity; Property; Proteins; Publications; Relative (related person); Research; Research Design; Research Methodology; Research Personnel; Research Support; Resources; Scientist; Signal Transduction; Site; Source; Structure; Students; Synaptic plasticity; Techniques; Testing; Time; Tissues; Water; Work; base; experience; improved; in vivo; innovation; insight; member; molecular recognition; novel; public health relevance; response; skills; symposium; tool

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.

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的分子水平结构和功能后果的化学工具。该拨款申请的总体目标是开发一种新方法，在体外模拟各种生理钙信号传导模式，并具有体内使用的潜力。该应用的中心假设是，已知响应光而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，以创建钙的可逆“笼”。这项研究的基本原理是，一旦开发出来，这种方法将用于破译钙信号的影响，最终深入了解人类的正常和不健康状况。因此，拟议的研究与 NIH 的使命相关。我们计划通过追求以下两个具体目标来测试我们的中心假设并实现此应用程序的目标。 1).提高萘并吡喃螯合剂的金属结合亲和力和 Ca2+ 选择性，以模拟生理条件下的钙信号。 2) 调整可逆光电开关的结合特性以获得更大幅度的振荡钙信号。该项目具有创新性，因为它将创建可用于研究动态钙信号传导的影响而无需启动整个信号转导级联的方法。拟议的研究意义重大，因为它有望提供一种化学工具，可用于增进对钙信号传导的理解以及阐明与钙信号传导相关的某些疾病的分子基础。