Traumatic Axonopathy in the CNS as Wallerian degeneration

中枢神经系统外伤性轴突病表现为沃勒变性

• 批准号: 10320956
• 负责人: VASSILIS E. KOLIATSOS
• 金额: $ 47.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320956
• 关键词: Affect; Atrophic; Axon; Behavior; Brain; CRISPR/Cas technology; Cells; Cessation of life; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Complement; Complementary DNA; Corticospinal Tracts; Development; Diffuse; Dominant-Negative Mutation; Future; Genetic; Goals; Hour; Impairment; Incidence; Injury; Instruction; Intervention; JNK-activating protein kinase; Knock-out; Knockout Mice; Laboratories; Lead; Leucine Zippers; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Genetics; Molecular Probes; Molecular Profiling; Molecular Target; Morphology; Motor; Motor Skills; Nerve Degeneration; Neuroanatomy; Neurons; Neuropathy; Outcome; Pathway interactions; Pharmacology; Phosphotransferases; Prevention; Prognosis; Research; Resolution; Role; Safety; Secondary to; Severities; Signal Pathway; Signal Transduction; Spinal; Sterility; System; Technology; Testing; Therapeutic Agents; Tracer; Translating; Trauma; Traumatic Brain Injury; Traumatic injury; Wallerian Degeneration; Work; axon injury; axonal degeneration; axonopathy; base; behavior test; clinically significant; conditional knockout; designer receptors exclusively activated by designer drugs; experimental study; genome editing; indexing; inhibitor; injured; jun Oncogene; kinase inhibitor; mechanical force; member; metabolomics; motor deficit; neuropathology; neuroprotection; neurotransmission; novel therapeutics; preservation; prevent; programs; repaired; response to injury; small molecule; small molecule inhibitor; synergism; therapy design; tool; white matter

PROJECT SUMMARY In this application we propose that traumatic axonal injury (TAI) leads to an active axonopathy with the molecular features of Wallerian degeneration and that targeting some of the relevant signals may protect axons as well as brain systems. This hypothesis is based on recent findings in our laboratory showing that axonal breakdown after diffuse TAI depends on the activation of Sterile Alpha and TIR Motif Containing 1 (SARM1) signaling and that molecular interventions to block SARM1 lead to significant gains in preserving axons and rescuing functions/behaviors that rely on axonal integrity. The case of TAI is unique in the sense that that many axons are only partially injured and are potentially salvageable, therefore blocking Wallerian-type self-destruction may afford long-term neuroprotection and change the prognosis of traumatic brain injury. Our proposal is organized in three specific aims. In Aim 1 we establish that TAI in an index CNS tract, i.e. the corticospinal system, leads to progressive axonopathy with the molecular signatures of Wallerian degeneration, i.e. activation of SARM1. In Aim 2 we ask whether axonal protection by genetic or pharmacological blockade of SARM1 signaling in the injured corticospinal tract translate into protection at the systems level, i.e. prevention of retrograde atrophy of corticospinal neurons, preservation of corticospinal connectivity and rescue of CST-dependent motor skills. In Aim 3 we explore the synergistic role of the mitogen-activated protein kinase (MAPK) pathway, specifically signaling by the dual leucine zipper kinase (DLK) and related leucine zipper kinase (LZK), in corticospinal axonal degeneration following TAI. The MAPK pathway signals general neuronal responses to injury and there is evidence that specific members of the pathway cooperate with SARM1-related signals in triggering or affecting the outcome of Wallerian degeneration. To achieve the previous aims, we use a complement of molecular genetic tools including knockout mice, dominant negative strategies and genome editing with CRISPR-Cas9, metabolomic assessments, CLARITY-based high-resolution neuropathology, structural and functional connectivity markers, behavioral testing, and small molecules as probes for molecular targets and also as therapeutic agents (the NAMPT inhibitor FK866 that serves as indirect inhibitor of SARM1 and the pan-Aurora inhibitor tozasertib that blocks DLK/LZK signaling). In summary, here we explore specific molecular mechanisms related to Wallerian degeneration and, in the course of doing this, we establish molecular targets for potential pharmacological interventions in traumatic brain injury.

项目摘要 在此应用中，我们建议创伤性轴突损伤（TAI）导致具有分子的活性轴突病变 Wallerian变性的功能以及针对某些相关信号的特征可能会保护轴突以及 大脑系统。该假设基于我们实验室中的最新发现，表明轴突故障 弥漫性之后，泰取决于无菌α的激活和包含1（sarm1）信号的TIR基序的激活 阻断SARM1的分子干预措施可在保存轴突和救援方面显着增长 依赖轴突完整性的功能/行为。 Tai的情况是独一无二的 只有部分受伤并有可能挽救，因此阻止沃勒人型自我毁灭 提供长期神经保护作用并改变脑外伤的预后。我们的建议是组织的 在三个具体目标中。在目标1中，我们确定了索引中心的TAI，即皮质脊髓系统 与Wallerian变性的分子特征进行进行性轴突病，即SARM1的激活。在 AIM 2我们询问轴突保护是通过遗传或药理学阻断SARM1信号传导 受伤的皮质脊髓道可以在系统一级的保护中转化为保护，即预防逆行萎缩 皮质脊髓神经元，皮质脊髓连通性的保存和CST依赖运动技能的营救。在 AIM 3我们探索有丝分裂原激活蛋白激酶（MAPK）途径的协同作用，特别是 双亮氨酸拉链激酶（DLK）和相关亮氨酸拉链激酶（LZK）的信号传导，在皮质脊髓轴突中 太极后的变性。 MAPK途径标志着一般神经元反应对损伤，并且有 该路径的特定成员在触发或影响时与SARM1相关信号合作 沃勒堕落的结果。为了实现先前的目标，我们使用分子的补充 遗传工具，包括淘汰小鼠，主要负面策略和CRISPR-CAS9的基因组编辑， 代谢组学评估，基于清晰的高分辨率神经病理学，结构和功能 连通性标记，行为测试和小分子作为分子靶标的探针，也是 治疗剂（NAMPT抑制剂FK866，可作为SARM1的间接抑制剂和Pan-aurora 阻止DLK/LZK信号传导的抑制剂Tozasertib。总而言之，我们在这里探索特定的分子机制 与Wallerian变性有关，在此过程中，我们建立了潜在的分子靶标 创伤性脑损伤的药理干预措施。