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The cell cycle in ototoxin induced hair cell death.

耳毒素中的细胞周期诱导毛细胞死亡。

基本信息

批准号：
7252025
负责人：
Neil Segil
金额：
$ 32.24万
依托单位：
HOUSE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7252025
关键词：
Abnormal Cell Address Adverse effects Aminoglycoside Antibiotics Aminoglycosides Animals Antibiotic Therapy Antibiotics Apoptosis Apoptotic Appearance Biological Assay Biological Models CDK2 gene CDK4 gene Caspase Cell Cycle Cell Cycle Progression Cell Death Cells Cessation of life Chromatin Cochlea Cochlear Implants Complement Cyclin D1 Cyclin-Dependent Kinase Gene Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Cyclins DNA Damage DNA biosynthesis DNA damage checkpoint Data Defect Effector Cell Elements Event Family Figs - dietary Gene Mutation Genes Genetic Goals Grant Green Fluorescent Proteins Hair Cells Hearing Aids Helper-Inducer T-Lymphocyte Human Immunohistochemistry In Vitro Individual Infection Knock-out Knockout Mice Lead Link Maintenance Mediating Mitotic Molecular Monitor Morphology Mus Mutate Mutation N-terminal Natural regeneration Neomycin Neurons Noise Numbers Organ Culture Techniques Organ of Corti Pan Genus Pathway interactions Personal Satisfaction Phosphotransferases Physiological Principal Investigator Process Prosthesis Reactive Oxygen Species Relative (related person)Research Personnel Resistance Role Sensory Hair Shock Signal Transduction Specificity Stress Suggestion TP53 gene Testing Transcriptional Activation Transducers Transgenic Mice Transgenic Organisms Up-Regulation Work base biological adaptation to stress cdc Genes cell injury cell killing cell type chemotherapeutic agent chemotherapy deafness forging genetic analysis hearing impairment in vivo inhibitor/antagonist mouse model neuron apoptosis novel olomoucine ototoxin programs research study response roscovitine stress-activated protein kinase 1 tool

项目摘要

DESCRIPTION (provided by applicant): This proposal is based on the novel observation that the cell cycle machinery in hair cells is activated following antibiotic administration. We hypothesize that this cell cycle reentry is intimately involved in regulating the subsequent cell death of hair cells. The importance of the cell cycle machinery in stress responses and cell death is well established. Our earlier work suggested a role for the cell cycle machinery, in particular the cyclin-dependent kinase (CDK) inhibitor p19lnk4d, in maintaining the non-dividing state of hair cells and thus in regulating the sensitivity to ototoxic stress and subsequent death. Preliminary results presented in this proposal confirm this suggestion. In response to neomycin, activation of the cell cycle is observed. In addition, inhibitors of the cell cycle machinery are shown to block cell death following administration of aminoglycoside antibiotics. To pursue these observations, we propose three specific aims incorporating a combined pharmacological and genetic approach. In Specific Aim 1, the effect of blocking specific cyclin-dependent kinase (CDK) activity on response to ototoxin will be tested. In Specific Aim 2, we will focus on the response of hair cells to ototoxins and attempt to tie this response to the activation of the cell cycle at the molecular level. Finally, in Specific Aim 3 we propose experiments to test the hypothesis that upon reentry into the cell cycle, hair cells activate the 'downstream' DNA damage checkpoint and that this is the, proximal inducer of the cell death machinery... Loss of sensory hair cells is the leading cause of deafness in humans. The mature mammalian cochlea cannot regenerate its complement of sensory hair cells and thus at present, the only treatment for deafness due to sensory hair cell loss is the use of prosthetics such as hearing aids and cochlear implants. Strategies to protect hair cells from ototoxin induced cell death would allow more aggressive use of chemotherapy agents and antibiotic treatment of infections that are now limited'by -their known ototoxic side effects.

描述（由申请方提供）：该提案基于新观察结果，即抗生素给药后毛细胞中的细胞周期机制被激活。我们推测，这种细胞周期折返密切参与调节随后的毛细胞死亡。细胞周期机制在应激反应和细胞死亡中的重要性已得到充分证实。我们早期的工作表明，细胞周期机制，特别是细胞周期蛋白依赖性激酶（CDK）抑制剂p19lnk4d，在维持毛细胞的非分裂状态，从而在调节耳毒性应激和随后的死亡的敏感性的作用。本提案中提出的初步结果证实了这一建议。响应于新霉素，观察到细胞周期的激活。此外，细胞周期机制的抑制剂显示在施用氨基糖苷类抗生素后阻断细胞死亡。为了追求这些观察结果，我们提出了三个具体的目标，结合药理学和遗传学的方法。在特异性目的1中，将检测阻断特异性细胞周期蛋白依赖性激酶（CDK）活性对耳毒素应答的影响。在具体目标2中，我们将重点关注毛细胞对耳毒素的反应，并试图在分子水平上将这种反应与细胞周期的激活联系起来。最后，在具体目标3中，我们提出了实验来验证这一假设，即在重新进入细胞周期时，毛细胞激活“下游”DNA损伤检查点，这是细胞死亡机制的近端诱导物。感觉毛细胞的丧失是人类耳聋的主要原因。成熟的哺乳动物耳蜗不能再生其感觉毛细胞的补充，因此目前，由于感觉毛细胞损失而导致的耳聋的唯一治疗方法是使用假体，例如助听器和耳蜗植入物。保护毛细胞免受耳毒素诱导的细胞死亡的策略将允许更积极地使用化疗剂和抗生素治疗感染，这些感染现在受到它们已知的耳毒性副作用的限制。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Early transcriptional response to aminoglycoside antibiotic suggests alternate pathways leading to apoptosis in sensory hair cells in the mouse inner ear.

DOI：
10.3389/fncel.2015.00190
发表时间：
2015
期刊：
Frontiers in cellular neuroscience
影响因子：
5.3
作者：
Tao L;Segil N
通讯作者：
Segil N

Mutations in Cockayne Syndrome-Associated Genes (Csa and Csb) Predispose to Cisplatin-Induced Hearing Loss in Mice.

科凯恩综合征相关基因（Csa 和 Csb）突变易导致顺铂引起的小鼠听力损失。

DOI：
10.1523/jneurosci.3890-15.2016
发表时间：
2016
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Rainey,RobertN;Ng,Sum-Yan;Llamas,Juan;vanderHorst,GijsbertusTJ;Segil,Neil
通讯作者：
Segil,Neil