HDAC6: a target for regeneration following injury in the nervous system

HDAC6：神经系统损伤后的再生目标

基本信息

批准号：
8415946
负责人：
Brett Cameron Langley
金额：
$ 38.67万
依托单位：
WINIFRED MASTERSON BURKE MED RES INST
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415946
关键词：
Acetylation Acetyltransferase Actins Acute Adult Affect Astrocytes Axon Cell Culture Techniques Cells Chondroitin Sulfate Proteoglycan Chronic Cytoskeleton Deacetylation Development Disease Dorsal Environment Enzymes Exposure to Failure Fiber Growth Histone Acetylation Histones In Vitro Injury Isoenzymes Lead Lysine Mediating Methods Microfluidics Microtubules Modeling Molecular Mus Myelin Myelin Associated Glycoprotein Natural regeneration Nervous system structure Neuraxis Neurites Neurons Neurosciences Outcome Paralysed Patients Play Process Property Protein Isoforms Proteins Publishing Rattus Recovery Recovery of Function Regulation Rodent Model Role Scheme Sensory Signal Transduction Spinal cord injury Testing Therapeutic Treatment Efficacy Tubulin Zinc axon growth axon regeneration central nervous system injury disability growth inhibitory proteins histone deacetylase 6 improved improved functioning in vivo inhibitor/antagonist injured injury and repair insight motor function recovery nervous system disorder neuronal cell body novel overexpression pre-clinical public health relevance receptor regenerative relating to nervous system response restoration therapeutic target transcriptional coactivator p75

项目摘要

DESCRIPTION (provided by applicant): Spinal cord Injury is a problem affecting millions worldwide. A dominant hypothesis in regenerative neuroscience is that patients with spinal cord injury suffer from permanent functional deficits and paralysis because of neural damage, but also because of a limited capacity of CNS axons to regenerate and restore lost neuronal connectivity. According to this scheme, a primary cause of failed regeneration is a limited intrinsic ability of adult neurons to regrow injured axons and the growth-hostile environment of the damaged cord. Several critical molecules that impede axon regeneration in the injury territory have been identified and include myelin-derived growth-inhibitory proteins such as myelin associated-glycoprotein (MAG) and reactive astrocyte-produced chondroitin sulfate proteoglycans (CSPGs). Myelin and astrocyte-derived inhibitory signals ultimately converge on the actin and microtubule cytoskeleton, affecting their stability, dynamics, and ability to direct axonal growth. We have found that specifically targeting histone deacetylase 6 (HDAC6) in neurons, using both pharmacological inhibitors and knockdown methods, can overcome the inhibitory effects of MAG or CSPGs to axon growth, in vitro. Using microfluidic chambers that isolate axons from the neuronal cell bodies we have determined that local processes in the axon mediate this effect. Consistent with this, we have found that HDAC6 inhibition or knockdown does not increase histone acetylation (a canonical function of pan-HDAC inhibitors that target multiple HDAC isozymes) and that recovery of growth can occur in the presence of a transcriptional inhibitor. A primary, and non-nuclear, function of HDAC6 is the deacetylation of 1-tubulin lysine 40 and, in turn, the modulation of microtubule dynamics. Given the role of the microtubule in axon growth, we hypothesize that HDAC6 plays a role in mediating a cell's response to myelin and astrocyte derived inhibitory signals via 1- tubulin deacetylation and microtubule destabilization. In the Specific Aims of this Application, we will examine the function of HDAC6, as well as the 1-tubulin acetylating enzyme, Elp3, in growth-inhibited axons. We will examine the extent to which their activities modulate the acetylation level of 1-tubulin and the role of 1-tubulin deacetylation in microtubule destabilization and axonal regeneration failure. We also will test whether HDAC6 plays a role in axon regeneration failure in vivo and whether increasing 1-tubulin acetylation by HDAC inhibition enhances axonal regeneration after spinal cord injury.

描述（由申请人提供）：脊髓损伤是一个影响全世界数百万人的问题。再生神经科学的一个主要假设是，脊髓损伤患者由于神经损伤而遭受永久性功能缺陷和瘫痪，但也因为中枢神经系统轴突再生和恢复失去的神经元连接的能力有限。根据该方案，再生失败的主要原因是成年神经元再生受损轴突的内在能力有限以及受损脊髓的生长不利环境。已经鉴定出几种阻碍损伤区域轴突再生的关键分子，包括髓磷脂衍生的生长抑制蛋白，例如髓磷脂相关糖蛋白（MAG）和反应性星形胶质细胞产生的硫酸软骨素蛋白聚糖（CSPG）。髓磷脂和星形胶质细胞衍生的抑制信号最终汇聚到肌动蛋白和微管细胞骨架上，影响它们的稳定性、动力学和指导轴突生长的能力。我们发现，使用药理学抑制剂和敲低方法特异性靶向神经元中的组蛋白脱乙酰酶 6 (HDAC6)，可以在体外克服 MAG 或 CSPG 对轴突生长的抑制作用。使用将轴突与神经元细胞体分离的微流体室，我们确定轴突中的局部过程介导了这种效应。与此一致的是，我们发现 HDAC6 抑制或敲低不会增加组蛋白乙酰化（针对多种 HDAC 同工酶的泛 HDAC 抑制剂的典型功能），并且在转录抑制剂存在的情况下可以发生生长恢复。 HDAC6 的主要非核功能是 1-微管蛋白赖氨酸 40 的脱乙酰化，进而调节微管动力学。鉴于微管在轴突生长中的作用，我们假设 HDAC6 通过 1-微管蛋白脱乙酰化和微管不稳定，在介导细胞对髓磷脂和星形胶质细胞衍生的抑制信号的反应中发挥作用。在本申请的具体目标中，我们将检查 HDAC6 以及 1-微管蛋白乙酰化酶 Elp3 在生长抑制的轴突中的功能。我们将研究它们的活性调节 1-微管蛋白乙酰化水平的程度以及 1-微管蛋白去乙酰化在微管不稳定和轴突再生失败中的作用。我们还将测试 HDAC6 是否在体内轴突再生失败中发挥作用，以及通过 HDAC 抑制增加 1-微管蛋白乙酰化是否会增强脊髓损伤后的轴突再生。