Regulation of Neuronal Survival by the Rit GTPase

Rit GTPase 对神经元存活的调节

基本信息

批准号：
8274683
负责人：
Douglas Allen Andres
金额：
$ 31.41万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8274683
关键词：
1-Phosphatidylinositol 3-Kinase Address Alzheimer&apos s Disease Apoptosis Apoptotic Biochemical Biological Biological Models Biology CREB1 gene Cataloging Catalogs Cell Death Cell Survival Cell model Cells Cellular Stress Cessation of life Complex Couples Coupling DNA Microarray Chip Data Development Disease Dominant-Negative Mutation Drosophila genus Epilepsy Family Family member Fostering Funding GTP-Binding Proteins Gene Expression Genes Genetic Transcription Goals Guanosine Triphosphate Phosphohydrolases HSPB1 gene Health Hippocampus (Brain)Human Huntington Disease Injury Knock-out Knockout Mice Ligands MAP Kinase Modules MAPK14 gene MAPK8 gene MEKs Malignant Neoplasms Mediating Microarray Analysis Molecular Nature Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuronal Differentiation Neurons Orthologous Gene Parkinson Disease Pathway interactions Pheochromocytoma Phosphotransferases Physiological Physiology Play Process Proteins Proto-Oncogene Proteins c-akt RPS6KA5 gene Reactive Oxygen Species Recovery Recruitment Activity Regulation Research Role Signal Pathway Signal Transduction Site Son of Sevenless Proteins Speed Stimulus Stress Stroke Structure of superior cervical ganglion Testing Therapeutic Therapeutic Intervention Transducers Transgenic Mice Transgenic Organisms Translating Withdrawal Work biological adaptation to stress cell growth regulation extracellular in vivo inhibitor/antagonist insight mitogen-activated protein kinase p38 mouse model neuronal survival neurotrophic factor novel novel therapeutics programs ras-Related G-Proteins repaired response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Signaling pathways that contribute to cell death/survival influence diseases including cancer and many neurodegenerative conditions. Elaborating signal transduction mechanisms that regulate these processes are thus important for understanding basic biology and for therapeutic intervention. Neurotrophins potently stimulate neuronal survival in part by activating the small GTP-binding protein Ras, which functions by translating neurotrophin-initiated signals into multiple signaling pathways, including PI-3 kinase/Akt and MEK/ERK, to promote survival. In the initial funding period it was proposed that a novel, and evolutionarily conserved group of Ras-related GTPases, including two mammalian proteins (Rit and Rin) and a single Drosophila ortholog (Ric), play critical roles in regulating apoptotic signaling. From this work, it is now clear that both Rit and Ric promote neuronal survival in a manner distinct from that of Ras. The original hypothesis is now expanded to address how these anti-apoptotic signaling cascades are regulated. The central hypothesis of this proposal is that the Rit GTPase functions as a molecular switch in neurons, responding to both apoptotic stresses and neurotrophin-initiated signals, to activate a distinct pro-survival signaling cascade that relies upon p38 MAP kinase signaling. Three specific aims are proposed: Aim 1 will characterize the ability of activated Rit to promote neuronal survival. In particular, we will assess the ability of Rit signaling to protect neurons from trophic factor-withdrawal mediated apoptosis. Using primary neurons from two transgenic mouse models either expressing activated Rit specifically in neurons or a homozygous Rit knockout mouse (developed during the previous period) it is now possible to analyze these critical issues. In addition, microarray analysis will be used to catalog the neuronal transcriptional program regulated by Rit signaling. Aim 2 will determine the regulatory mechanism that couples NGF-stimulated TrkA to Rit activation and the nature of Rit-dependent regulation of the p38 MAP kinase cascade. Aim 3 will explore the critical signaling pathways utilized for Rit anti-apoptotic signaling. In particular, Rit-mediated activation of both the p38- MSK1/2 kinase cascade and CREB transcriptional pathways appear to play central roles and will be tested using a combination of both cell model systems and primary neurons. Importantly, data developed since the previous review suggests that a second novel Rit-p38-HSP27-MK2 pathway may stimulate AKT signaling to afford neuronal protection. In summary, these studies will establish a role for Rit in neuronal survival. Regulation of this novel Ras-related G-protein may have a pronounced impact on neuronal physiology and would make Rit and its effectors, potential targets for the development of new therapeutic strategies. PUBLIC HEALTH RELEVANCE: The death of neurons causes or contributes to various neurodegenerative disorders including stroke, epilepsy, Parkinson's disease, Huntington's disease, and Alzheimer's disease. Importantly, we have discovered a protein that promotes neuronal survival, protecting neurons from potentially lethal stimuli. Understanding the mechanism that foster neuronal survival is of fundamental importance to the development of treatment strategies for these disorders. Thus, the goal of this research is to speed progress toward therapeutic exploitation of this protein in neurodegenerative disease.

描述（由申请人提供）：有助于细胞死亡/生存影响包括癌症和许多神经退行性疾病的疾病的信号通路。因此，阐述调节这些过程的信号转导机制对于理解基本生物学和治疗干预非常重要。神经营养蛋白通过激活小的GTP结合蛋白Ras来有效刺激神经元存活，该蛋白Ras通过将神经营养蛋白引起的信号转化为多个信号通路，包括PI-3激酶/AKT和MEK/MEK/ERK，以促进生存。在最初的资金期间，有人提出了一种新颖的，进化保守的与RAS相关的GTPase，包括两种哺乳动物蛋白（RIT和RIN）和一个单一的果蝇直系同源物（RIC），在调节凋亡信号传导中起关键作用。从这项工作中，现在很明显RIT和RIC都以与RA的不同方式促进了神经元的生存。现在扩展了原始假设，以解决如何调节这些抗凋亡信号传导级联。该提案的中心假设是RIT GTPase充当神经元中的分子转换，响应凋亡应激和神经营养蛋白引起的信号，以激活一个依赖于p38 MAP激酶信号传导的独特的蛋白卵巢信号级联。提出了三个具体目标：AIM 1将表征活化RIT促进神经元存活的能力。特别是，我们将评估RIT信号传导保护神经元免受营养因子介导的细胞凋亡的能力。使用来自两种表达活化RIT的转基因小鼠模型的原发性神经元，或者使用纯合RIT基因敲除小鼠（在上一个时期开发），现在可以分析这些关键问题。此外，微阵列分析将用于分类由RIT信号调节的神经元转录程序。 AIM 2将确定伴侣NGF刺激的TRKA的调节机制以及p38 MAP激酶级联反RIT依赖性调节的性质。 AIM 3将探索用于RIT抗凋亡信号传导的临界信号通路。特别是，RIT介导的p38-MSK1/2激酶级联反应和CREB转录途径的激活似乎起着中心作用，并将使用细胞模型系统和原代神经元的组合进行测试。重要的是，由于上一篇评论表明，第二个新型RIT-P38-HSP27-MK2途径可能会刺激AKT信号传导以获得神经元保护。总而言之，这些研究将确定RIT在神经元存活中的作用。对这种新型RAS相关的G蛋白的调节可能会对神经元生理产生明显的影响，并将使RIT及其效应子和开发新的治疗策略的潜在目标。公共卫生相关性：神经元的死亡原因或导致各种神经退行性疾病，包括中风，癫痫，帕金森氏病，亨廷顿氏病和阿尔茨海默氏病。重要的是，我们发现了一种促进神经元存活的蛋白质，保护神经元免受潜在致命刺激。了解促进神经元生存的机制对于这些疾病的治疗策略的发展至关重要。因此，这项研究的目的是加快在神经退行性疾病中对该蛋白质的治疗剥削的进步。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rit GTPase regulates a p38 MAPK-dependent neuronal survival pathway.

DOI：
10.1016/j.neulet.2012.10.036
发表时间：
2012-12-07
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Cai W;Rudolph JL;Sengoku T;Andres DA
通讯作者：
Andres DA

Pituitary adenylate cyclase-activating polypeptide 38-mediated Rin activation requires Src and contributes to the regulation of HSP27 signaling during neuronal differentiation.

垂体腺苷酸环化酶激活多肽 38 介导的 Rin 激活需要 Src，并有助于神经元分化过程中 HSP27 信号传导的调节。

DOI：
10.1128/mcb.02193-07
发表时间：
2008
期刊：
Molecular and cellular biology
影响因子：
5.3
作者：
Shi,Geng-Xian;Jin,Ling;Andres,DouglasA
通讯作者：
Andres,DouglasA

Rit signaling contributes to interferon-gamma-induced dendritic retraction via p38 mitogen-activated protein kinase activation.

DOI：
10.1111/j.1471-4159.2008.05708.x
发表时间：
2008-12
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Andres DA;Shi GX;Bruun D;Barnhart C;Lein PJ
通讯作者：
Lein PJ

Rit GTPase signaling promotes immature hippocampal neuronal survival.

DOI：
10.1523/jneurosci.0375-12.2012
发表时间：
2012-07-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Cai W;Carlson SW;Brelsfoard JM;Mannon CE;Moncman CL;Saatman KE;Andres DA
通讯作者：
Andres DA

An evolutionarily conserved Rit GTPase-p38 MAPK signaling pathway mediates oxidative stress resistance.