Genetic evaluation of the p53 cell death pathway in spinal muscular atrophy (SMA)

脊髓性肌萎缩症 (SMA) 中 p53 细胞死亡途径的遗传评估

• 批准号: 8702765
• 负责人: George Z Mentis
• 金额: $ 24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702765
• 关键词: Adverse drug effect; Affect; Alleles; Antisense Oligonucleotides; Apoptosis; Behavior; Behavioral; Birth; Body Weight; Breathing; Breeding; Cell Death; Cessation of life; Child; Childhood; Clinical Trials; Complement; DNA Damage; Data; Defect; Denervation; Disease; Disease Pathway; Evaluation; Exhibits; Functional disorder; Future; Genes; Genetic; Health; Hereditary Disease; Human; In Situ Hybridization; In Vitro; Investigation; Knock-out; Knowledge; Lead; Link; Longevity; Measures; Medial; Modeling; Molecular; Motor; Motor Neurons; Mus; Muscle; Muscle Weakness; Muscular Atrophy; Neurons; Nuclear; Outcome Measure; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Prevention; Process; Protein Deficiency; Protein p53; Role; SMN protein (spinal muscular atrophy); Sampling; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Muscular Atrophy; Staging; Symptoms; Synapses; System; Tamoxifen; Testing; Therapeutic; Time; Tissues; Up-Regulation; Vision; Weight Gain; base; disease phenotype; improved; in vivo; inhibitor/antagonist; limb movement; motor disorder; motor neuron degeneration; mouse model; neuromuscular transmission; neuron loss; new therapeutic target; novel; novel strategies; pifithrin; prevent; research study; restoration; selective expression; small molecule; stretch reflex; success; tool

DESCRIPTION (provided by applicant): The childhood genetic disease spinal muscular atrophy (SMA) leads to progressive muscle weakness and loss of motor neurons in the spinal cord. In all cases this results from reductions in the levels of the ubiquitous SMN (survival of motor neuron protein) and current therapeutic approaches focused on upregulating SMN have shown success in mouse models and will be tested in patients. However, these remain untested strategies and it is not probable that upregulation of SMN in patients that already show symptoms will alone be sufficient to correct all functional deficits. There is therefore a need to better understand the disease mechanism and define new approaches to therapy based on this knowledge. The current vision of SMA is that defects in spinal motor circuits precede degeneration and death of motor neurons but that both contribute to the disease phenotype. Clinically, the most affected motor neurons are those that innervate proximal muscles. We have shown that these medial motor column (MMC) motor neurons are selectively lost in the SMA-Δ7 mouse model. By gene profiling of MMC motor neurons before they degenerate, we identified the tumor suppressor p53 and its downstream effector PERP (p53 apoptosis effector related to PMP-22) as candidate intermediates in the motor neuron death pathway. In support of this hypothesis, administration of an inhibitor of p53 to SMA- Δ7 mice significantly increased weight gain and prevented motor neuron loss. However, the effects are transient and the drug does not correct the pronounced behavioral deficits. To determine whether this incomplete rescue reflects limitations of the drug itself, we propose to evaluate the role of p53 and PERP genetically by crossing SMA mice to conditional knockouts for each, using a novel inducible motor neuron-specific Cre driver. The results will help to define the role of the first cell death pathway deduced by examination of the most vulnerable motor neurons in SMA, and should allow us to determine the contribution of motor neuron cell death to the overall phenotype of the SMA mice. In the future this may lead to the definition of novel therapeutic targets for prevention of motor neuron death in affected patients.

描述(申请人提供)：儿童遗传性疾病脊髓性肌萎缩症(SMA)导致进行性肌肉无力和脊髓运动神经元的丧失。在所有病例中，这都是由于普遍存在的运动神经元存活蛋白(SMN)水平的降低，以及目前专注于上调SMN的治疗方法在小鼠模型中显示出成功，并将在患者中进行测试。然而，这些仍然是未经测试的策略，而且已经出现症状的患者上调SMN不太可能足以纠正所有的功能缺陷。因此，有必要更好地了解疾病的机制，并在此基础上确定新的治疗方法。目前SMA的设想是，脊髓运动神经回路的缺陷先于运动神经元的退化和死亡，但这两者都导致了疾病的表型。临床上，受影响最大的运动神经元是那些支配近端肌肉的运动神经元。我们已经证明在SMA-Δ7小鼠模型中，这些内侧运动柱运动神经元选择性地丢失。通过对MMC运动神经元变性前的基因图谱分析，我们确定肿瘤抑制因子P53及其下游效应因子PERP(与PMP-22相关的P53凋亡效应因子)是运动神经元死亡途径的候选中间产物。为了支持这一假设，给SMA-Δ7小鼠注射P53抑制剂显著增加了体重增加并防止了运动神经元的丢失。然而，这种效果是暂时的，这种药物并不能纠正明显的行为缺陷。为了确定这种不完全的挽救是否反映了药物本身的局限性，我们建议使用一种新的可诱导运动神经元特异性CRE驱动程序，通过将SMA小鼠与条件基因敲除小鼠进行杂交，从遗传学角度评估P53和PERP的作用。这一结果将有助于确定通过对SMA中最脆弱的运动神经元的检查而得出的第一个细胞死亡途径的作用，并将使我们能够确定运动神经元细胞死亡对SMA小鼠整体表型的贡献。在未来，这可能会导致新的治疗靶点的定义，以防止受影响患者的运动神经元死亡。