Genetic Analysis of Ras and G Protein Function

Ras 和 G 蛋白功能的遗传分析

• 批准号: 7786841
• 负责人: LARRY FEIG
• 金额: $ 52.88万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7786841
• 关键词: Adolescence; Adolescent; Adolescent Behavior; Affect; Animal Genetics; Animals; Binding; Biochemical; Biochemical Pathway; Biological Assay; Brain; Calcium; Calcium Signaling; Complex; Couples; DNA Methylation; Defect; Disease; Environment; Exercise; Exposure to; Family; Fright; Future; GTP-Binding Proteins; Generations; Genes; Genetic; Glutamate Receptor; Goals; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Hippocampus (Brain); Inherited; Knockout Mice; Learning; Life; Long-Term Depression; Long-Term Potentiation; MAP Kinase Signaling Pathways; MAPK14 gene; Mediating; Memory; Mental disorders; Mitogen-Activated Protein Kinases; Molecular; Mus; Mutation; Neurologic; Neurons; Pathway interactions; Persons; Phosphotransferases; Play; Predisposition; Proteins; Reading; Role; Signal Pathway; Signal Transduction; Socialization; Sorting - Cell Movement; Specificity; Synaptic plasticity; Testing; base; early adolescence; genetic analysis; genetic regulatory protein; genome wide association study; insight; juvenile animal; mature animal; mitogen-activated protein kinase p38; next generation; novel; novel strategies; offspring; protein function; public health relevance; ras Proteins; receptor; receptor binding; research study

DESCRIPTION (provided by applicant): The execution of complex functions and their breakdown in disease involves the interplay between an animal's genetics and environment. The overall goals of this proposal are to reveal how Ras-family GTPases influence signaling networks that control synaptic plasticity, and how an "enriched environment" (EE) alters these networks to change the way synaptic plasticity is induced in adolescent mice and remarkably, across generations. One focus of this proposal is on GRF1 and GRF2, which form a family of multi-catalytic, calcium- stimulated, guanine nucleotide exchange factors that have the potential to activate both Ras and Rac GTPases. Despite these similarities, we found that GRF1 and GRF2 promote opposing forms of synaptic plasticity induced by NMDA-type glutamate receptors (NMDA-Rs) beginning at early adolescence. GRF1 promotes long-term depression (LTD), while GRF2 promotes long-term potentiation (LTP), at least in part, because they regulate different MAP kinases. The experiments outlined below combine genetic, biochemical and electrophysiological studies to reveal how GRF1 and GRF2 respond to different upstream signals, and how signaling downstream from their Ras- and Rac-activating domains is differentially regulated in the hippocampus. These experiments will add new insight into how specificity is achieved in neuronal signal transduction. They will also add significantly to our understanding of the molecular basis of LTP and LTD induction. Defects in these well-established cellular paradigms of learning and memory are thought to contribute to a variety of neurological and mental health disorders. A second focus of this proposal is how environmental stimulation, involving exposure to novel objects, enhanced socialization and voluntary exercise particularly during pre-adolescence, changes the way LTP is induced. We discovered that adolescent enrichment unlocks a previously unidentified latent signaling pathway that promotes LTP in mice and rescues defective LTP and contextual fear memory in GRF knockout mice. Even more dramatic is our finding that these effects of pre-adolescent enrichment are passed on to the next generation through their adolescence. The experiments described will use multiple approaches to reveal how this novel EE-gated signaling pathway promotes LTP, and how EE unlocks this cascade to affect synaptic plasticity and memory across generations. A better understanding of the trans-generational effects of the environment on brain function may reveal new approaches to overcome neurological and mental health disorders. PUBLIC HEALTH RELEVANCE: Although a person's genetic blueprint strongly contributes to his/her susceptibility to disease, it is clear that the environment in which one lives influences how that blueprint is read. Our study investigates how Ras proteins contribute to biochemical pathways in the brain that mediate learning and memory. It also explores how a stimulating "enriched environment", particularly during pre-adolescence, changes these biochemical pathways in normal animals, and compensates for a genetic defect in Ras signaling. Remarkably, we find that juvenile enrichment affects not only animals directly exposed to it, but also their future offspring through adolescence. A full understanding of the trans-generational effects of the environment on brain function may reveal new approaches to overcome neurological and mental health disorders.

描述（由申请人提供）：复杂功能的执行及其在疾病中的细分涉及动物的遗传学和环境之间的相互作用。该提案的总体目标是揭示RAS家庭GTPases如何影响控制突触可塑性的信号网络，以及“丰富的环境”（EE）如何改变这些网络，以改变青少年小鼠中引起的突触可塑性的方式，并且在各个一代中都显着。 该提案的一个重点是GRF1和GRF2，它们形成了一个多催化，钙刺激的鸟嘌呤核苷酸交换因子，具有激活RAS和RAC GTPase的潜力。尽管有这些相似性，我们发现GRF1和GRF2促进了NMDA型谷氨酸受体（NMDA-RS）诱导的相反形式的突触可塑性，从青春期开始。 GRF1促进了长期抑郁症（LTD），而GRF2至少部分地促进了长期增强（LTP），因为它们调节了不同的MAP激酶。下面概述的实验结合了遗传，生化和电生理研究，以揭示GRF1和GRF2如何响应不同的上游信号，以及在Hippocampus中对其RAS和RAS激活结构域的下游信号传导如何受到差异调节。这些实验将增加有关神经元信号转导的特异性的新见解。它们还将大大增加我们对LTP和LTD诱导分子基础的理解。这些知名的学习和记忆范围内的缺陷被认为会导致各种神经系统和心理健康障碍。 该提案的第二个重点是环境刺激如何涉及暴露于新物体，增强社会化和自​​愿运动，尤其是在青春期前，改变了LTP的诱导方式。我们发现，青少年富集解锁了先前未知的潜在信号通路，该信号通路促进了小鼠的LTP并营救有缺陷的LTP和GRF敲除小鼠的上下文恐惧记忆。我们的发现，更加戏剧化的是，青春期前富集的这些影响通过青春期传递给了下一代。所描述的实验将使用多种方法来揭示这种新型的EE门控信号通路如何促进LTP，以及EE如何解锁该级联反应以影响世代相传的突触可塑性和记忆。对环境对脑功能的跨代作用的更好理解可能会揭示克服神经和心理健康障碍的新方法。 公共卫生相关性：尽管一个人的遗传蓝图对他/她对疾病的敏感性有很大贡献，但很明显，人们生活的环境会影响阅读该蓝图的方式。我们的研究研究了RAS蛋白如何促进大脑中介导学习和记忆的生化途径。它还探讨了刺激“富集环境”，尤其是在青春期前如何改变正常动物中的这些生化途径，并补偿RAS信号传导中的遗传缺陷。值得注意的是，我们发现少年富集不仅影响着直接暴露于它的动物，而且会影响其未来的后代。对环境对脑功能的跨代作用的充分理解可能揭示了克服神经和心理健康障碍的新方法。