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Targeting Atr to promote regeneration and functional recovery after neural injury

靶向 Atr 促进神经损伤后的再生和功能恢复

基本信息

批准号：
10450101
负责人：
Yuanquan Song
金额：
$ 37.63万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450101
关键词：
ATR gene Afferent Neurons Axon Behavior Behavioral Assay CHEK1 gene Cell Cycle Cell physiology Cellular Stress Chromatin Clinical Trials Cues DNA Damage DNA Single Strand Break DNA damage checkpoint Data Drosophila genus Excision Failure Functional Regeneration Genetic Genetic Screening Goals Homologous Gene Image Impairment In Vitro Injury Ion Channel Lead Link Location Mechanical Stress Mechanoreceptors Mediating Modeling Molecular Multiple Sclerosis Natural regeneration Nerve Degeneration Nerve Regeneration Neuraxis Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Neuronal Injury Neurons Operative Surgical Procedures Paralysed Pathologic Pathway interactions Patients Pattern Peripheral Pharmaceutical Preparations Pharmacology Phenotype Piezo ion channels Population Property Protein-Serine-Threonine Kinases Proteins Public Health Recovery Recovery of Function Refractory Regenerative capacity Regenerative pathway Regenerative research Role Signal Pathway Spinal Cord Lesions Spinal Ganglia Spinal cord injury System Testing Therapeutic Touch sensation Translating Trauma Work anti-cancer axon injury axon regeneration base cancer therapy cell type central nervous system injury combinatorial design disability druggable target effective therapy endoplasmic reticulum stress extracellular fly gain of function improved inhibitor insight knock-down loss of function mechanical force mechanical signal mechanical stimulus molecular targeted therapies mutant nerve injury nervous system disorder neuron regeneration new therapeutic target nociceptive response novel overexpression regenerative relating to nervous system repaired response sciatic nerve young adult

项目摘要

Failure of damaged axons to regenerate and reestablish functional circuitry is the primary cause that results in permanent disabilities after central nervous system (CNS) injury, and is also a major factor contributing to the non-reversible neurologic dysfunction seen in neurodegenerative diseases. Of approximately 1.9% of the U.S. population with paralysis, some 1,275,000 are paralyzed as the result of a spinal cord injury (SCI). SCIs frequently result in at least some incurable impairment even with the best possible treatment and patients with complete injuries recover very little lost function. Under pathological situations such as multiple sclerosis, the second most common neurological disorder leading to disability in young adults, failure of damaged axons to regenerate contributes to neurologic abnormalities. Despite ample efforts in the past few decades, which have led to the discoveries of extracellular factors that impede, and intrinsic pathways in mature neurons that diminish the regenerative capacity of axons, effective therapies have not emerged given the fact that simply removing those inhibitory cues confers limited regrowth and that our understanding of neurons’ intrinsic regenerative properties still remains incomplete, indicating that additional regulatory machinery must be in place. This highlights the urgent need to identify novel molecular targets for therapy. With the goal to find novel factors essential for CNS axon regeneration, we have utilized a Drosophila sensory neuron injury model that resembles mammalian injury at the phenotypical and molecular level in a candidate- based genetic screen, and identified the Piezo-Atr (Ataxia telangiectasia and Rad3 related) pathway as inhibitors for axon regeneration. This proposal aims to determine the cellular and molecular mechanisms underlying Piezo- Atr’s function in flies and to elucidate the role of the mammalian Atr after peripheral or spinal cord injury. Atr is an essential component of the DNA damage response and also responds to mechanical force. This pathway has never been implicated in axon regeneration, and our study will thus provide exciting insights into the potential links among axon injury, DNA damage response, mechanosensation and regeneration, and will open new avenues of research for regeneration and spinal cord injury. Taking advantage of the power of fly genetics to identify novel factors and the mammalian injury model, this strategy offers a unique opportunity to gain insights into the repertoire of regeneration regulators, which may drive novel treatments to promote recovery in patients with neural injury or neurodegenerative diseases.

受损轴突再生和重建功能回路的失败是导致神经系统损伤的主要原因。中枢神经系统（CNS）损伤后的永久性残疾，并且也是导致神经变性疾病中所见的不可逆神经功能障碍的主要因素。在瘫痪的人口中，约有1，275，000人因脊髓损伤（SCI）而瘫痪。经常导致至少一些无法治愈的损害，即使有最好的治疗和患者完全损伤恢复很少失去的功能。在病理情况下，如多发性硬化症，第二种最常见的神经系统疾病，导致年轻人残疾，受损的轴突无法再生有助于神经异常。尽管在过去的几十年里，导致了细胞外因子的发现，阻碍，和内在的途径，在成熟的神经元，减少轴突的再生能力，有效的治疗方法还没有出现，因为简单地去除这些抑制性信号赋予有限的再生，我们对神经元内在再生的理解财产仍然不完整，这表明必须建立更多的监管机制。突出了迫切需要确定新的分子靶点的治疗。为了寻找中枢神经系统轴突再生所必需的新因子，我们利用果蝇感觉神经系统，神经元损伤模型，在表型和分子水平上类似于哺乳动物损伤，基于遗传筛选，并确定了压电Atr（共济失调毛细血管扩张和Rad 3相关）途径作为抑制剂该建议旨在确定Piezo-100的细胞和分子机制， Atr在果蝇中的功能，并阐明哺乳动物Atr在外周或脊髓损伤后的作用。这是DNA损伤反应的重要组成部分，也对机械力有反应。从来没有涉及轴突再生，因此我们的研究将提供令人兴奋的见解的潜力轴突损伤，DNA损伤反应，机械感觉和再生之间的联系，并将开辟新的再生和脊髓损伤的研究途径。利用苍蝇遗传学的力量来识别新的因素和哺乳动物损伤模型，这一策略提供了一个独特的机会，以获得见解再生调节剂的全部功能，这可能会推动新的治疗方法，以促进患者的康复神经损伤或神经退行性疾病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Non-canonical role of the ATR pathway in axon regeneration as a mechanosensitive brake.

DOI：
10.4103/1673-5374.335807
发表时间：
2022-11
期刊：
NEURAL REGENERATION RESEARCH
影响因子：
6.1
作者：
Li, Feng;Song, Yuanquan
通讯作者：
Song, Yuanquan

Optical control of ERK and AKT signaling promotes axon regeneration and functional recovery of PNS and CNS in Drosophila.

DOI：
10.7554/elife.57395
发表时间：
2020-10-06
期刊：
eLife
影响因子：
7.7
作者：
Wang Q;Fan H;Li F;Skeeters SS;Krishnamurthy VV;Song Y;Zhang K
通讯作者：
Zhang K

Mechanosensitive Ion Channels, Axonal Growth, and Regeneration.

DOI：
10.1177/10738584221088575
发表时间：
2023-08
期刊：
NEUROSCIENTIST
影响因子：
5.6
作者：
Miles, Leann;Powell, Jackson;Kozak, Casey;Song, Yuanquan
通讯作者：
Song, Yuanquan

Drosophila Laser Axotomy Injury Model to Investigate RNA Repair and Splicing in Axon Regeneration.

DOI：
10.1007/978-1-0716-3012-9_22
发表时间：
2023
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
通讯作者：

Glia instruct axon regeneration via a ternary modulation of neuronal calcium channels in Drosophila.

DOI：
10.1038/s41467-023-42306-2
发表时间：
2023-10-14
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Trombley, Shannon;Powell, Jackson;Guttipatti, Pavithran;Matamoros, Andrew;Lin, Xiaohui;O'Harrow, Tristan;Steinschaden, Tobias;Miles, Leann;Wang, Qin;Wang, Shuchao;Qiu, Jingyun;Li, Qingyang;Li, Feng;Song, Yuanquan
通讯作者：
Song, Yuanquan