Plaque detection with the hydrocyanines

描述（由申请人提供）：动脉粥样硬化和动脉粥样硬化相关并发症，如心脏病发作、中风和心绞痛，是西方世界死亡的主要原因，并且非常需要有效的治疗。限制动脉粥样硬化治疗的一个关键问题是无法诊断具有高生长和破裂风险的动脉粥样硬化斑块，也称为“活性”斑块。活性氧（ROS）的过度产生是动脉粥样硬化斑块生长和破裂所必需的，使ROS成为“活动”斑块的极好诊断标志物。本申请的目的是开发一种新的荧光造影剂家族，称为氢菁，其具有对颈动脉中动脉粥样硬化斑块中的ROS成像并检测斑块活性所需的物理和化学性质。氢菁是我们实验室最近开发的一种新的荧光染料家族，其可以检测纳摩尔浓度的ROS，具有范围为570-810 nm的可调谐发射波长，并且在氧化后在细胞内积累。我们的方法是图像ROS在小鼠和兔子的颈动脉，患有血管损伤和动脉粥样硬化，与氢菁。该提议的中心假设是：氢菁具有检测颈动脉中的氧化应激和检测斑块活性所需的物理和化学性质。这一假设是基于我们的初步数据，这表明，氢菁可以检测超氧阴离子和氢氧根自由基在细胞培养物中，在组织样品和第一次在体内。本提案的总体目标将通过以下三个具体目标来测试我们的中心假设来实现：具体目标I：使用动力学同位素效应优化氢菁具体目标II：检测颈动脉损伤小鼠模型中的ROS产生具体目标III：在兔动脉粥样硬化模型中检测动脉粥样硬化组织体内ROS的产生，在患病的人冠状动脉中的体内本发明中的实验将确定氢花青是否可以使动脉粥样硬化斑块中的ROS成像并检测小鼠和兔中的斑块活性。该提案中的实验是创新的，因为它们将导致开发一种可以在体内首次对ROS进行成像的造影剂。这一提议也很重要，因为它将产生一类新的诊断方法，有可能诊断出有心脏病发作和中风风险的患者。此外，许多其他疾病也与ROS的过度产生有关，例如癌症和神经退行性疾病;因此，我们预计这项提案的结果将影响医学和生物学的几个领域。公共卫生相关性：该提案中的实验将导致一类新的荧光染料的开发，称为氢菁，它可以在体内成像活性氧。氢菁的主要应用是诊断有心脏病发作和中风风险的患者。许多其他疾病，如癌症和关节炎，也可以通过成像反应物质来诊断;因此，我们预计这项提议的结果将影响医学和生物学的几个领域。

DESCRIPTION (provided by applicant): Atherosclerosis and atherosclerosis related complications such as heart attack, stroke, and angina, are the leading cause of death in the western world, and effective treatments are greatly needed. A key issue limiting the treatment of atherosclerosis is an inability to diagnose atherosclerotic plaques that have a high risk of growing and rupturing, also known as "active" plaques. The overproduction of reactive oxygen species (ROS) is necessary for the growth and rupture of atherosclerotic plaques, making ROS an excellent diagnostic marker for "active" plaques. The objective of this application is to develop a new family of fluorescent contrast agents, termed the hydrocyanines, which have the physical and chemical properties needed to image ROS in atherosclerotic plaques, in the carotid artery, and detect plaque activity. The hydrocyanines are a new family of fluorescent dyes, recently developed in our laboratory, which can detect ROS at nanomolar concentrations, have tunable emission wavelengths ranging from 570-810 nm, and accumulate within cells after oxidation. Our approach is to image ROS in the carotid artery of mice and rabbits, suffering from vascular injury and atherosclerosis, with the hydrocyanines. The central hypothesis of this proposal is that: The hydrocyanines have the physical and chemical properties needed to detect oxidative stress in the carotid artery and detect plaque activity. This hypothesis is based on our preliminary data, which demonstrates that the hydrocyanines can detect superoxide and the hydroxide radical in cell culture, in tissue samples and for the first time in vivo. The overall objective of this proposal will be accomplished by testing our central hypothesis through the following three Specific Aims; Specific Aim I: Optimize the hydrocyanines using the kinetic isotope effect Specific Aim II: Detect ROS production in a murine model of carotid artery injury Specific Aim III: Detect ROS production by atherosclerotic tissues in vivo in a rabbit model of atherosclerosis and ex-vivo in diseased human coronary arteries The experiments in this proposal will determine if the hydrocyanines can image ROS in atherosclerotic plaques and detect plaque activity in mice and rabbits. The experiments in this proposal are innovative because they will lead to the development of a contrast agent that can image ROS, in vivo, for the first time. This proposal is also significant because it will generate a new class of diagnostics, which have the potential to diagnose patients at risk of developing heart attacks and strokes. Furthermore, numerous other diseases are also associated with an overproduction of ROS, such as cancer and neurodegenerative disease; we therefore anticipate that the results of this proposal will impact several areas of medicine and biology. PUBLIC HEALTH RELEVANCE: Project Narrative The experiments in this proposal will lead to the development of a new class of fluorescent dyes, termed the hydrocyanines, which can image reactive oxygen species in vivo. The major applications of the hydrocyanines are to diagnose patients at risk of developing heart attacks and strokes. Numerous other diseases such as cancer and arthritis can also be diagnosed by imaging reactive species; we therefore anticipate that the results of this proposal will impact several areas of medicine and biology.