Studies on the role of retinoid signaling and microRNAs in adult newt spinal cord regeneration

类维生素A信号和microRNA在成体蝾螈脊髓再生中作用的研究

• 批准号: 2802-2012
• 负责人: Carlone, Robert
• 金额: $ 1.89万
• 依托单位: Brock University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=520514
• 关键词: Studies; role; retinoid; signaling; microRNAs

Nerves in the spinal cord of adult mammals and birds fail to regenerate after injury and correcting this failure is a major goal of neuroscience. Adult newts and salamanders, however, exhibit remarkable regenerative capacity of a number of tissues, including the spinal cord and parts of the brain. Our main research aim is to understand the molecular and cellular mechanisms that underlie functional spinal cord regeneration in the newts as a prelude to determining why mammals fail in this process. To this end, we have examined the role of all-trans retinoic acid (RA), a small, fat-soluble molecule synthesized from vitamin A, in this process. We have recently shown that a protein receptor for RA, retinoic acid receptor beta (RARß), is an important regulator of early events in the regenerating newt spinal cord. However, we do not know what factors are affected by RA-RARß signaling in this process. To regenerate the spinal cord, multiple signaling pathways must be activated or repressed simultaneously, involving numerous molecular changes in RA-responsive cells. We hypothesize that microRNAs (miRNAs), small, non-protein coding RNAs, capable of regulating the expression of many genes coordinately, may be important targets of RA signaling. Our specific objectives are threefold: 1. To identify novel miRNAs synthesized as a consequence of damage to the spinal cord as well as those whose production is affected by retinoid treatment. 2. To determine the cells in the regenerating spinal cord that make these miRNAs and identify their potential messenger RNA targets and functions. 3. Finally, to analyze the mechanism by which RA can guide growing nerves to their appropriate "target" cells in regenerating spinal cords. These studies would represent the first comprehensive analysis of the role of miRNAs in regulating RA signaling in a regenerating spinal cord model. It is hoped that our results will provide a more thorough understanding of the molecular events controlling spinal cord regeneration in newts, with the goal of applying this knowledge to the as yet intractable process of spinal cord repair in higher vertebrates, including humans.

成年哺乳动物和鸟类的脊髓神经在受伤后无法再生，纠正这种失败是神经科学的主要目标。然而，成年蝾螈和蝾螈在许多组织中表现出显着的再生能力，包括脊髓和大脑的一部分。我们的主要研究目标是了解蝾螈脊髓功能性再生的分子和细胞机制，作为确定哺乳动物在这一过程中失败的前奏。 为此，我们研究了全反式维甲酸（RA），一种小的，脂溶性分子合成的维生素A，在这个过程中的作用。我们最近发现，RA的蛋白质受体，视黄酸受体β（RARDR），是再生蝾螈脊髓早期事件的重要调节因子。 然而，我们不知道在这一过程中哪些因素受到RA-RAR信号的影响。为了再生脊髓，必须同时激活或抑制多个信号通路，涉及RA反应细胞中的许多分子变化。我们推测，microRNAs（miRNAs），小的，非蛋白质编码的RNA，能够协调调节许多基因的表达，可能是RA信号转导的重要靶点。我们的具体目标有三个方面：1.鉴定由于脊髓损伤而合成的新型miRNAs以及其产生受到类维生素A治疗影响的miRNAs。2.确定再生脊髓中产生这些miRNAs的细胞，并确定其潜在的信使RNA靶点和功能。3.最后，分析RA在脊髓再生中引导生长的神经到达合适的“靶”细胞的机制。这些研究将代表在再生脊髓模型中miRNAs在调节RA信号传导中的作用的第一次全面分析。希望我们的研究结果将提供一个更彻底的了解控制脊髓再生的蝾螈的分子事件，与应用这些知识的目标尚未棘手的过程中，在高等脊椎动物，包括人类的脊髓修复。