MKRN3 imprinting, regulation, and action in the control of puberty
MKRN3 印记、调节和控制青春期的作用
基本信息
- 批准号:10249285
- 负责人:
- 金额:$ 24.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:15qAdultAllelesAwardCandidate Disease GeneCell LineCell NucleusChildChildhoodChromosomesComplementComplexCuesDNA MethylationDNA Sequence AlterationDataData AnalysesDefectDelayed PubertyDevelopmentDiagnosisDiseaseEmbryoEnvironmental Risk FactorFamilyFrequenciesGene ExpressionGeneticGenetic TechniquesGoalsGonadotropin Hormone Releasing HormoneHormone secretionHospitalsHumanHypothalamic structureIn VitroInheritedInvestigationKISS1 geneKlinefelter&aposs SyndromeKnowledgeLearningLifeLinkMeasuresMentorsMethylationMolecularMolecular GeneticsMusNeonatalNeuronsNeurosecretory SystemsNutritionalPathway interactionsPatientsPhasePhysiciansPhysiologic pulsePrecocious PubertyPubertyRegulationReproductionResearchRiskRoleScientistSequence AnalysisSexual ReproductionStructureSupervisionTissuesTrainingTraining ProgramsTranslatingVocational GuidanceWomanWorkbasebisulfitecareercohortepigenetic regulationexperienceexperimental studygenetic associationhypothalamic pituitary gonadal axisimprintin vivoin vivo Modelinduced pluripotent stem cellinfancyinsightknock-downloss of function mutationmaternal imprintmedical schoolsmethylation patternmouse modelnovelphysical processpsychologicpubertal timingtooltranscriptome sequencingtranslational scientistubiquitin-protein ligase
项目摘要
ABSTRACT
Puberty and reproduction are controlled by the hypothalamic-pituitary-gonadal (HPG) axis. The HPG axis is
active during the embryonic and neonatal stages of human life but then suppressed during childhood. The re-
activation of HPG axis results in puberty initiation. The precise mechanisms that regulate GnRH secretion to
constrain the HPG axis during infancy and childhood and subsequently trigger the initiation of puberty remain
elusive. The timing of puberty is associated with risks of subsequent disease and it is crucial to identify what
elicits puberty initiation. Complex interactions among genetic, nutritional, and environmental factors influence
pubertal initiation. We have recently identified loss-of-function mutations in MKRN3 in families with central
precocious puberty (CPP). MKRN3 is located on chromosome 15q and is maternally imprinted, expressed only
from the paternally inherited allele. The association of genetic mutations in MKRN3 with CPP is indisputable;
however, the possibility of imprinting abnormalities in MKRN3 as a cause of pubertal disorders has not been
explored. Epigenetic regulation of MKRN3 may be a link between environmental cues and pubertal timing. This
proposal will investigate the MKRN3 imprinting profile during pubertal development and determine if MKRN3
imprinting abnormalities are associated with pubertal disorders; and study the molecular mechanisms by which
MKRN3 regulates GnRH secretion. To this end, four distinct but complementary specific aims are proposed.
The mentored phase of the proposal will be carried out under Dr. Ursula Kaiser's supervision at Brigham and
Women's Hospital/Harvard Medical School. The aims of the K99 mentored phase are to: 1) Investigate the
MKRN3 methylation profile in different phases of human life and confirm the methylation pattern in mouse
tissues; and 2) Characterize the cellular and molecular mechanisms by which MKRN3 regulates GnRH
secretion in vitro. This training will provide expertise in DNA methylation studies, in hiPSC experiments, and in
RNA-Seq data analysis. The elucidation of the MKRN3 imprinting profile during normal pubertal development
and an understanding of the actions of MKRN3 in hypothalamic neurons will provide a strong base of
knowledge for the transition to the independent R00 phase of the award. Building on previous experience, the
aims of the R00 independent phase are to: 3) Investigate if abnormalities in MKRN3 imprinting are associated
with pubertal disorders; 4) Extend investigation of mechanisms of action of MKRN3 to in vivo mouse models.
This award includes a well-structured training program that includes course work and seminar learning
experiences. Completion of this project will lead to a better understanding of the molecular roles of MKRN3 in
the regulation of GnRH secretion and advance our fundamental knowledge of MKRN3 imprinting. The
successful completion of the aims of this proposal will bring new insights in the neuroendocrine regulation of
GnRH secretion and enable me to establish my career as a successful independent translational investigator.
抽象的
青春期和生殖由下丘脑-垂体-性腺(HPG)轴控制。 HPG 轴为
在人类生命的胚胎和新生儿阶段活跃,但在儿童时期被抑制。那里-
HPG 轴的激活导致青春期开始。调节 GnRH 分泌的精确机制
在婴儿期和儿童期限制 HPG 轴,随后触发青春期的开始
难以捉摸。青春期的时间与随后疾病的风险相关,确定哪些因素至关重要
引发青春期启动。遗传、营养和环境因素之间复杂的相互作用影响
青春期启动。我们最近在患有中枢神经系统疾病的家族中发现了 MKRN3 的功能丧失突变。
性早熟(CPP)。 MKRN3 位于染色体 15q 上,具有母系印记,仅表达
来自父系遗传的等位基因。 MKRN3 基因突变与 CPP 的关联是无可争议的。
然而,MKRN3 印记异常作为青春期疾病原因的可能性尚未得到证实。
探索过。 MKRN3 的表观遗传调控可能是环境因素和青春期时间之间的联系。这
该提案将调查青春期发育期间的 MKRN3 印记概况,并确定 MKRN3 是否
印记异常与青春期疾病有关;并研究其分子机制
MKRN3 调节 GnRH 分泌。为此,提出了四个不同但互补的具体目标。
该提案的指导阶段将在布里格姆和布莱根大学的 Ursula Kaiser 博士的监督下进行。
妇女医院/哈佛医学院。 K99 指导阶段的目标是: 1) 调查
人类生命不同阶段的MKRN3甲基化谱并确认小鼠的甲基化模式
纸巾; 2) 表征 MKRN3 调节 GnRH 的细胞和分子机制
体外分泌。该培训将提供 DNA 甲基化研究、hiPSC 实验和
RNA-Seq 数据分析。正常青春期发育过程中 MKRN3 印记谱的阐明
了解 MKRN3 在下丘脑神经元中的作用将为以下方面提供坚实的基础:
过渡到该奖项的独立 R00 阶段的知识。根据以往的经验,
R00 独立阶段的目标是: 3) 调查 MKRN3 印记异常是否相关
患有青春期疾病; 4) 将 MKRN3 作用机制的研究扩展到体内小鼠模型。
该奖项包括一个结构良好的培训计划,其中包括课程作业和研讨会学习
经验。该项目的完成将有助于更好地了解 MKRN3 在
GnRH 分泌的调节并增进我们对 MKRN3 印记的基础知识。这
该提案目标的成功完成将为神经内分泌调节带来新的见解
GnRH 分泌使我能够成为一名成功的独立转化研究者。
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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Ana Paula de Abreu e Silva Metzger其他文献
Ana Paula de Abreu e Silva Metzger的其他文献
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{{ truncateString('Ana Paula de Abreu e Silva Metzger', 18)}}的其他基金
MKRN3 imprinting, regulation, and action in the control of puberty
MKRN3 印记、调节和控制青春期的作用
- 批准号:
10025263 - 财政年份:2019
- 资助金额:
$ 24.89万 - 项目类别:
MKRN3 imprinting, regulation, and action in the control of puberty
MKRN3 印记、调节和控制青春期的作用
- 批准号:
10021765 - 财政年份:2019
- 资助金额:
$ 24.89万 - 项目类别:
Exploring the Role of the Prokineticin System in Human Reproduction
探索前动力素系统在人类生殖中的作用
- 批准号:
8321284 - 财政年份:2012
- 资助金额:
$ 24.89万 - 项目类别:
Exploring the Role of the Prokineticin System in Human Reproduction
探索前动力素系统在人类生殖中的作用
- 批准号:
8490178 - 财政年份:2012
- 资助金额:
$ 24.89万 - 项目类别:
Exploring the Role of the Prokineticin System in Human Reproduction
探索前动力素系统在人类生殖中的作用
- 批准号:
8733447 - 财政年份:2012
- 资助金额:
$ 24.89万 - 项目类别:
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