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.

摘要