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.

受损轴突无法再生和恢复功能电路的失败是导致的主要原因中枢神经系统（CNS）损伤后的永久残疾，也是导致神经退行性疾病中非可逆性神经功能障碍的主要因素。美国约1.9％瘫痪的人口，由于脊髓损伤（SCI），大约1,275,000人瘫痪。 Scis 即使有最佳的潜在治疗和患者完全伤害恢复了很少的功能。在多发性硬化症等病理情况下，第二个最常见的神经系统疾病导致年轻人混乱，损伤轴突失败再生有助于神经系统异常。尽管在过去的几十年中，尽管有足够的努力导致障碍细胞外因素的发现，以及成熟神经元中的内在途径轴突的再生能力，有效的疗法尚未出现那些抑制性提示赋予了限制的再生，并且我们对神经元内在再生的理解属性仍然不完整，表明必须有其他监管机械。这强调迫切需要鉴定新的分子靶标的治疗。为了找到CNS轴突再生必不可少的新因素，我们使用了果蝇感觉神经元损伤模型，类似于在表型和分子水平的哺乳动物损伤中基于遗传筛选，并确定了压电 - ATR（共济失调telangiectia和rad3相关）作为抑制剂用于轴突再生。该提案旨在确定压电的基础的细胞和分子机制 ATR在苍蝇中的功能，并阐明外周或脊髓损伤后哺乳动物ATR的作用。 ATR是 DNA损伤响应的重要组成部分，也响应机械力。这条路在轴突再生中从未暗示过，因此我们的研究将为潜力提供令人兴奋的见解轴突损伤，DNA损伤响应，机制和再生之间的联系，并将开放新的再生研究和脊髓损伤的研究途径。利用蝇遗传学的力量来识别新因素和哺乳动物损伤模型，该策略提供了一个独特的机会来获得见解进入再生调节剂的曲目，这可能会驱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

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

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