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（由申请人提供）：儿童遗传性疾病脊髓性肌萎缩症（SMA）导致进行性肌无力和脊髓运动神经元丢失。在所有情况下，这都是由于普遍存在的SMN（运动神经元存活蛋白）水平降低所致，目前专注于上调SMN的治疗方法已在小鼠模型中取得成功，并将在患者中进行测试。然而，这些仍然是未经测试的策略，并且在已经显示症状的患者中SMN的上调不太可能单独足以纠正所有功能缺陷。因此，有必要更好地了解疾病的机制，并根据这些知识定义新的治疗方法。SMA目前的观点是脊髓运动回路的缺陷先于运动神经元的变性和死亡，但两者都有助于疾病表型。临床上，受影响最大的运动神经元是那些支配近端肌肉的神经元。我们已经表明，这些内侧运动柱（MMC）运动神经元在SMA-Δ7小鼠模型中选择性丢失。通过MMC运动神经元退化前的基因谱分析，我们确定了肿瘤抑制因子p53及其下游效应子PERP（p53凋亡效应子与PMP-22相关）作为运动神经元死亡途径中的候选中间体。为了支持这一假设，向SMA- Δ7小鼠施用p53抑制剂显著增加了体重增加并防止了运动神经元损失。然而，这种作用是短暂的，药物不能纠正明显的行为缺陷。为了确定这种不完全的救援是否反映了药物本身的局限性，我们建议使用一种新的诱导型运动神经元特异性Cre驱动程序，通过将SMA小鼠与每个小鼠的条件性基因敲除进行遗传学评估p53和PERP的作用。这些结果将有助于确定通过检查SMA中最脆弱的运动神经元推导出的第一个细胞死亡途径的作用，并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目标的定义，以预防运动神经元死亡的患者。