NEUROENDOCRINOLOGY OF PUBERTY AND SEXUAL DEVELOPMENT
青春期和性发育的神经内分泌学
基本信息
- 批准号:8357881
- 负责人:
- 金额:$ 5.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-05-01 至 2012-04-30
- 项目状态:已结题
- 来源:
- 关键词:AstrocytesCell Signaling ProcessCellsCommunicationEpidermal Growth Factor ReceptorErbB4 geneExcitatory Amino AcidsFemaleFundingGenesGlutamatesGoalsGrantHypothalamic structureIntercellular Adhesion MoleculesLigandsMediatingMetalloproteasesMusNational Center for Research ResourcesNeuroendocrinologyNeurogliaNeuronsNeurosecretory SystemsPathway interactionsPrimatesPrincipal InvestigatorProcessPubertyReceptor Protein-Tyrosine KinasesRegulator GenesResearchResearch InfrastructureResourcesSexual DevelopmentSignaling MoleculeSourceSystemTestingTimeTranscriptional RegulationUnited States National Institutes of Healthcosthomeodomainintercellular communicationnovelreceptor
项目摘要
This subproject is one of many research subprojects utilizing the resources
provided by a Center grant funded by NIH/NCRR. Primary support for the subproject
and the subproject's principal investigator may have been provided by other sources,
including other NIH sources. The Total Cost listed for the subproject likely
represents the estimated amount of Center infrastructure utilized by the subproject,
not direct funding provided by the NCRR grant to the subproject or subproject staff.
This is a revised renewal application aimed at elucidating the neuroendocrine
mechanisms underlying the initiation of female puberty. During the last funding
period we examined the hypothesis that the activation of LHRH secretion at puberty
requires a cell-cell communication process provided by structurally and functionally
connected neuronal and glial subsets of the hypothalamus. We also began testing
the hypothesis that neuron-glia bidirectional communication, and hence the pubertal
process itself, is under the transcriptional control of "upstream" regulatory genes.
We established the initial framework supporting both concepts by: a) defining erbB-1
and erbB-4 tyrosine kinase receptors as major components of the communication
pathway used by glial cells to facilitate LHRH release, b) identifying
ionotropic/metabotropic receptors as signaling molecules used by glutamatergic
neurons to coordinate the facilitatory transsynaptic and glial input to LHRH neurons,
and c) defining the homeodomain gene TTF-1 as an example of an upstream
hierarchy of genes involved in the transcriptional control of puberty. In addition to
accomplishing these goals we identified two new components of the cell-cell signaling
process underlying erbB receptor-mediated glia-neuron bidirectional communication,
and discovered a novel gene that might represent a second upstream component of
the hypothalamic regulatory network controlling female sexual development. We now
propose studies to define the importance of these newly discovered systems in
neuroendocrine glia-neuronal communication and the impact they may exert on the
initiation of female puberty. To this end, the following aims are proposed: 1) To test
the hypothesis that TACE, a metalloproteinase involved in the ectodomain cleavage
of erbB ligands and erbB receptors, is required for excitatory amino acids to induce
glial TGFa release, and thus it is important for the neuron-glia mediated control of
puberty. 2) To test the hypothesis that glial expression of SynCAM, an intercellular
adhesion molecule found at reduced levels in astrocytes of erbB-4-deficient mice, is
involved in the glial-neuron control of female puberty. 3) To test the hypothesis that
TTF-1, a homeodomain gene required for the normal timing of female puberty, is an
upstream coordinator of the glial-neuronal interactions underlying the pubertal
activation of LHRH secretion. 4) To examine the hypothesis that a novel gene, termed
EAP-1 (Enhanced At. Puberty-1) belongs - along with TTF-1 - to the hierarchy of
controlling genes involved in the transcriptional regulation of the pubertal process.
这个子项目是许多利用资源的研究子项目之一
由NIH/NCRR资助的中心拨款提供。子项目的主要支持
而子项目的主要调查员可能是由其他来源提供的,
包括其它NIH来源。 列出的子项目总成本可能
代表子项目使用的中心基础设施的估计数量,
而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。
这是一份修订后的更新申请,旨在阐明神经内分泌
女性青春期开始的潜在机制。在最后一次融资中
我们研究了青春期LHRH分泌的激活
需要细胞间的通讯过程,
连接下丘脑的神经元和神经胶质亚群。我们也开始测试
神经元-胶质细胞双向通讯的假设,从而青春期
过程本身是在“上游”调控基因的转录控制下。
我们建立了支持这两个概念的初始框架:a)定义erbB-1
和erbB-4酪氨酸激酶受体作为通讯的主要成分,
神经胶质细胞用于促进LHRH释放的途径,B)鉴定
促离子型/促代谢型受体作为信号传导分子
神经元协调易化的跨突触和神经胶质输入到LHRH神经元,
和c)将同源结构域基因TTF-1定义为上游同源结构域的实例,
参与青春期转录控制的基因层次。除了
为了实现这些目标,我们发现了细胞间信号传导的两个新成分,
erbB受体介导的神经胶质-神经元双向通讯的基础过程,
发现了一个新的基因,它可能代表了
控制女性性发育的下丘脑调节网络。我们现在
提出研究,以确定这些新发现的系统的重要性,
神经内分泌胶质细胞-神经元通讯及其对神经内分泌系统的影响
女性青春期的开始。为此,提出了以下目标:1)测试
TACE是一种参与胞外域切割的金属蛋白酶,
erbB配体和erbB受体,是兴奋性氨基酸诱导
神经胶质细胞TGF α的释放,因此它是重要的神经元-胶质细胞介导的控制,
青春期2)为了验证SynCAM(一种细胞间粘附分子)在胶质细胞中的表达,
在erbB-4缺陷小鼠的星形胶质细胞中发现的水平降低的粘附分子,
参与女性青春期的神经胶质神经元控制。3)为了验证这个假设,
TTF-1是女性青春期正常发育所需的同源结构域基因,
青春期神经胶质-神经元相互作用的上游协调者
LHRH分泌的激活。4)为了检验一种新的基因,
EAP-1(增强型)青春期-1)属于-沿着与TTF-1 -的层次,
参与青春期过程转录调控的控制基因。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sergio R Ojeda其他文献
Sergio R Ojeda的其他文献
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{{ truncateString('Sergio R Ojeda', 18)}}的其他基金
Altering Energy Balance by Systemic Delivery of RNAi to the Neuroendocrine Brain
通过将 RNAi 系统性递送至神经内分泌脑来改变能量平衡
- 批准号:
8539523 - 财政年份:2012
- 资助金额:
$ 5.82万 - 项目类别:
Altering Energy Balance by Systemic Delivery of RNAi to the Neuroendocrine Brain
通过将 RNAi 系统性递送至神经内分泌脑来改变能量平衡
- 批准号:
8427058 - 财政年份:2012
- 资助金额:
$ 5.82万 - 项目类别:
NOVEL MECHANISMS UNDERLYING THE TRANSSYNAPTIC CONTROL OF LHRH RELEASE
LHRH 释放的跨突触控制的新机制
- 批准号:
8357725 - 财政年份:2011
- 资助金额:
$ 5.82万 - 项目类别:
MOLECULAR AND STRUCTURAL BASES OF HYPOTHALAMIC PUBERTY
下丘脑青春期的分子和结构基础
- 批准号:
8357754 - 财政年份:2011
- 资助金额:
$ 5.82万 - 项目类别:
RNA INTERFERENCE THERAPY FOR HUNTINGTON'S DISEASE: STUDIES IN NON-HUMAN PRIMATES
亨廷顿病的 RNA 干扰疗法:在非人类灵长类动物中的研究
- 批准号:
8357819 - 财政年份:2011
- 资助金额:
$ 5.82万 - 项目类别:
INTRODUCING STABLE INFERTILITY BY RNA INTERFERENCE
通过 RNA 干扰引入稳定的不孕症
- 批准号:
8357818 - 财政年份:2011
- 资助金额:
$ 5.82万 - 项目类别:














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