Identifying novel regenerative treatments for CNS injury in adult mammals

确定成年哺乳动物中枢神经系统损伤的新型再生疗法

• 批准号: 10735524
• 负责人: SHUXIN LI
• 金额: $ 49.9万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735524
• 关键词: Actomyosin; Adult; Axon; Binding; Cervical; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Cytoskeletal Proteins; Cytoskeleton; Disabled Persons; Dorsal; Environment; Failure; Gene Targeting; Genes; Genetic; Growth; Growth Cones; Individual; Knockout Mice; Lesion; Locomotor Recovery; Mammals; Microfilaments; Microtubules; Modeling; Molecular Target; Motor; Mus; Myosin Type II; Natural regeneration; Neuronal Injury; Neurons; Nonmuscle Myosin Type IIA; Nonmuscle Myosin Type IIB; Paralysed; Pathway interactions; Patients; Peptides; Pilot Projects; Population; Proteins; Recovery; Recovery of Function; Rodent; Role; Sensory; Signal Pathway; Signal Transduction; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Synapsins; Systemic Therapy; Therapeutic; Thoracic spinal cord structure; Tracer; Translating; Work; Zinc Fingers; antagonist; axon growth; axon injury; axon regeneration; axonal degeneration; cell growth; central nervous system injury; combinatorial; conditional knockout; design; effective therapy; inhibitor; injury and repair; mutant; neuronal growth; neurotransmission; non-muscle myosin; novel; pharmacologic; regenerative approach; regenerative treatment; repaired; safety assessment; targeted agent; therapeutic gene; transcription factor; translational study

Abstract We propose to study whether targeting both the transcription factor ZNF362 and cytoskeletal non-muscle myosin IIA and IIB (NMIIA&B) will promote better axon regeneration and functional recovery after spinal cord injury (SCI) than either approach alone. After SCI, severed axons fail to regenerate largely because of the reduced intrinsic growth capacity of adult CNS neurons and the poor environment for axon extension. Treatments to recover paralysis and other lost functions are not available and patients with SCI are often permanently disabled. Many genes have been determined to control the regrowth failure of mature neurons, but none have been translated to clinical use. There is a persistent need to identify better gene targets and therapeutic strategies. ZNF362 is highly expressed in the CNS, but its major function in mammals remains largely unknown. The PI’s group generated ZNF362 conditional knockout (cKO) mice and designed novel small peptides to block ZNF362 function selectively. Our pilot studies suggest that ZNF362 strongly suppresses the growth capacity of CNS neurons in adult rodents. After CNS injury, various inhibitory molecules around the lesion activate neuronal RhoA, which, in turn, activates cytoskeletal NMIIA&B to condense actin filaments and restricts microtubule protrusion and axon elongation. Because neuronal cytoskeleton is the major machinery to drive axon growth and the converging targets of multiple signaling pathways that control axon growth, manipulating neuronal cytoskeleton is also very attractive to promote significant CNS axon regeneration. We hypothesize that inhibiting both ZNF362 and NMIIA&B represents a dual approach for enhancing neuronal growth capacity and reducing environmental inhibition around the lesion. We propose to dissect potential critical roles of ZNF362 and NMIIA&B for controlling regrowth of mature CNS neurons and to develop novel and effective strategies for promoting CNS axon regeneration. We aim to stimulate robust axon regrowth and functional recovery in SCI rodents by suppressing these genes using cKO mice and new selective antagonist peptides designed in our lab. In Aim 1, we will study whether transgenically deleting ZNF362 and NMIIA&B acts synergistically to promote axon regeneration and recovery in adult mice with SCI. Aim 2 proposes to determine whether blocking individual ZNF362 and NMIIA&B signals pharmacologically with novel selective antagonists promotes axon regeneration and recovery in adult rodents with SCI. In Aim 3, we plan to develop combination therapies that block both ZNF362 and NMIIA&B signals, aiming to yield robust axon regrowth and functional recovery in adult rodents with SCI. Based on the promising results of our pilot studies, we anticipate that our novel regenerative strategies will significantly advance our ability to treat SCI. If our peptides are successful with rodent SCI models, we plan to move this work to peptide safety assessments and further translational studies (e.g., cervical/chronic SCI and clinical trials). Therefore, this project may facilitate identifying novel molecular targets for CNS repair and highly effective strategies for treating CNS lesions.

抽象的 我们建议研究是否靶向转录因子ZnF362和细胞骨架非肌肉 肌球蛋白IIA和IIB（NMIIA和B）将促进脊髓后更好的轴突再生和功能恢复 受伤（SCI）比单独的方法。 SCI之后，严重的轴突无法再生 成人中枢神经系统神经元的内在生长能力降低和轴突延伸的环境较差。治疗 恢复瘫痪和其他功能丢失，SCI患者通常是永久的 禁用。许多基因已决定控制成熟神经元的遗憾失败，但没有 被翻译成临床用途。持续需要确定更好的基因靶标和治疗 策略。 ZnF362在中枢神经系统中高度表达，但其在哺乳动物中的主要功能在很大程度上尚不清楚。 PI的组产生了Znf362有条件的敲除（CKO）小鼠，并设计了新型的小胡椒粉来阻止 Znf362函数有选择性。我们的试点研究表明，Znf362强烈抑制了 成人啮齿动物中的CNS神经元。 CNS损伤后，病变周围的各种抑制分子激活神经元 Rhoa又激活细胞骨架NMIIA和B以凝结肌动蛋白丝并限制微管 突出和轴突伸长。因为神经元细胞骨架是驱动轴突生长和 控制轴突生长，操纵神经元的多个信号通路的融合目标 细胞骨架对于促进明显的CNS轴突再生也非常有吸引力。我们假设抑制 ZnF362和NMIIA＆B都代表了增强神经元生长能力和降低的双重方法 病变周围的环境抑制。我们建议剖析ZnF362和NMIIA和B的潜在关键作用 控制成熟的中枢神经系统神经元的遗憾，并制定新颖有效的策略来促进中枢神经系统 轴突再生。我们旨在通过通过 使用CKO小鼠和我们实验室中设计的新的选择性拮抗剂肽抑制这些基因。在AIM 1中， 我们将研究跨科删除ZnF362和NMIIA和B是否具有协同作用以促进轴突 SCI成年小鼠的再生和恢复。目标2确定是否阻止个人的建议 ZNF362和NMIIA和B的NMIIA和B信号用新颖的选择性拮抗剂来促进轴突再生 和SCI成年啮齿动物的恢复。在AIM 3中，我们计划开发结合疗法，以阻止两者 ZNF362和NMIIA和B信号，旨在在成年啮齿动物的稳健轴突改革和功能恢复中产生 科学。根据我们的试点研究的承诺结果，我们预计我们的新型再生策略将会 显着提高了我们治疗科学的能力。如果我们的Petides成功使用了啮齿动物科学模型，我们计划 将这项工作转移到肽安全评估和进一步的翻译研究中（例如，宫颈/慢性SCI和 临床试验）。因此，该项目可能有助于确定CNS修复和 治疗中枢神经系统病变的高效策略。