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破坏涉及动物遗传和环境之间的相互作用。这项提案的总体目标是揭示Ras家族GTP酶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，以改变青春期小鼠中突触可塑性的诱导方式，并显着地跨代。 该建议的一个焦点是GRF 1和GRF 2，它们形成具有激活Ras和Rac GTP酶的潜力的多催化、钙刺激的鸟嘌呤核苷酸交换因子家族。尽管有这些相似之处，我们发现GRF 1和GRF 2促进相反形式的突触可塑性诱导的NMDA型谷氨酸受体（NMDA-Rs）在青春期早期开始。GRF 1促进长时程抑制（LTD），而GRF 2促进长时程增强（LTP），至少部分是因为它们调节不同的MAP激酶。下面概述的实验结合了联合收割机遗传学、生物化学和电生理学研究，以揭示GRF 1和GRF 2如何响应不同的上游信号，以及它们的Ras和Rac激活结构域下游的信号传导如何在海马中受到差异调节。这些实验将为神经元信号转导中特异性是如何实现的提供新的见解。他们也将大大增加我们对LTP和LTD诱导的分子基础的理解。这些完善的学习和记忆细胞模式的缺陷被认为是导致各种神经和心理健康障碍的原因。 本建议的第二个重点是环境刺激，包括接触新的物体，加强社会化和自愿锻炼，特别是在青春期前，如何改变LTP的诱导方式。我们发现，青少年丰富解锁了一个以前未识别的潜在信号通路，促进LTP小鼠和救援缺陷的LTP和上下文的恐惧记忆GRF敲除小鼠。更戏剧性的是，我们发现青春期前丰富的这些影响会通过青春期传递给下一代。所描述的实验将使用多种方法来揭示这种新的EE门控信号通路如何促进LTP，以及EE如何解锁这种级联以影响突触可塑性和跨代记忆。更好地了解环境对大脑功能的跨代影响可能会揭示克服神经和心理健康障碍的新方法。 公共卫生关系：虽然一个人的遗传蓝图对他/她对疾病的易感性有很大的贡献，但很明显，一个人所生活的环境会影响如何阅读蓝图。我们的研究调查了Ras蛋白如何促进大脑中介导学习和记忆的生化途径。它还探讨了一个刺激的“丰富的环境”，特别是在青春期前，如何改变正常动物的这些生化途径，并弥补Ras信号传导的遗传缺陷。值得注意的是，我们发现，少年丰富不仅影响直接暴露于它的动物，而且还影响他们未来的后代通过青春期。充分了解环境对大脑功能的跨代影响可能会揭示克服神经和心理健康障碍的新方法。