Modulation of atherosclerosis by cannabinoid type 2 receptor

描述（由申请人提供）：动脉粥样硬化的特征是脂肪、胆固醇和免疫细胞在动脉壁上积聚形成斑块。当斑块表面变弱时，它会变得不稳定，破裂会导致心脏病发作或中风，这是美国人死亡的主要原因。本研究的长期目标是确定调节动脉粥样硬化斑块的细胞机制，以寻找治疗动脉粥样硬化的新方法。大麻素是与大麻中的活性成分相关的化合物，通过与被称为大麻素受体的细胞表面受体结合来发挥作用。最近的研究表明大麻素受体在许多不同的炎症条件下失调，包括动脉粥样硬化。缺乏2型大麻素受体（CB2）的小鼠会形成动脉粥样硬化斑块，并伴有稳定性降低的证据。然而，CB2在动脉粥样硬化不同阶段的确切功能尚不清楚，也不清楚靶向CB2是否会引发疾病进展或对斑块稳定性提供保护作用。本研究的总体目标是明确CB2在动脉粥样硬化中的功能，并确定选择性靶向CB2对动脉粥样硬化易感小鼠斑块的影响。核心假设是巨噬细胞CB2依赖性过程影响斑块稳定性，并且CB2选择性化合物的管理将对动脉粥样硬化提供有益作用。为了验证这一假设，我们提出了以下具体目标：1)确定cb2对动脉粥样硬化易感小鼠病变稳定性的依赖作用，2)确定cb2对小鼠动脉粥样硬化病变钙化机制的依赖作用，以及3)确定参与cb2对小鼠动脉粥样硬化依赖作用的细胞类型。每个目标都将使用缺乏CB2的动脉粥样硬化易感小鼠进行测试，并使用选择性激活或抑制CB2的化合物治疗动脉粥样硬化易感小鼠。这项研究具有创新性，因为目前还没有关于CB2在晚期动脉粥样硬化中的作用或CB2选择性化合物如何影响动脉粥样硬化的数据。最终，从该项目中获得的知识将通过提供必要的信息来确定CB2是否是治疗人类动脉粥样硬化的潜在新疗法设计的可行靶点，从而推进动脉粥样硬化研究领域。

DESCRIPTION (provided by applicant): Atherosclerosis is characterized by the build up of fat, cholesterol, and immune cells in the walls of arteries to form plaques. When the surface of a plaque weakens, it can become unstable and rupture producing a heart attack or stroke, the leading cause of death in the US. The long-term goal of this research is to identify cellular mechanisms modulating atherosclerotic plaque in order to find new ways of treating atherosclerosis. Cannabinoids are compounds related to the active ingredient in marijuana and exert their effects by binding to cell surface receptors called cannabinoid receptors. Recent studies have shown cannabinoid receptors are dysregulated in a number of different inflammatory conditions, including atherosclerosis. Mice lacking the type 2 cannabinoid receptor, known as CB2, develop atherosclerotic plaques with evidence of reduced stability. However, the precise functions of CB2 in different stages of atherosclerosis are unclear, and it is unknown if targeting CB2 will trigger disease progression or provide a protective effect on plaque stability. The overall objectives of this research are to define the functions of CB2 in atherosclerosis and determine the effects of selectively targeting CB2 on plaques in atherosclerosis-prone mice. The central hypothesis is that macrophage CB2- dependent processes affect plaque stability, and that administration of CB2-selective compounds will provide beneficial effects on atherosclerosis. To test this hypothesis we propose the following specific aims: 1) Identify CB2-dependent effects on lesion stability in atherosclerosis-prone mice, 2) Identify CB2-dependent effects on atherosclerotic lesion calcification mechanisms in mice, and 3) Identify the cell types contributing to CB2-dependent effects on atherosclerosis in mice. Each aim will be tested using atherosclerosis-prone mice which lack CB2 and by treating atherosclerosis-prone mice with compounds to selectively activate or inhibit CB2. This research is innovative because no data currently exist regarding the effects of CB2 in advanced atherosclerosis or how CB2-selective compounds will affect atherosclerosis. Ultimately, the knowledge gained from this project will advance the field of atherosclerosis research by providing information necessary to determine if CB2 is a viable target for the design of potentially new therapies to treat atherosclerosis in humans.