GENE DOSAGE IN MAMMALIAN SEXUAL DEVELOPMENT
哺乳动物性发育中的基因剂量
基本信息
- 批准号:7955696
- 负责人:
- 金额:$ 0.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-01 至 2010-07-31
- 项目状态:已结题
- 来源:
- 关键词:AreaCandidate Disease GeneChromosomes, Human, Pair 11ClassificationComputer Retrieval of Information on Scientific Projects DatabaseDefectDevelopmentDiagnostic ProcedureDiseaseEmbryoEventFemaleFrequenciesFunctional disorderFundingGene DosageGenesGeneticGoalsGonadal structureGrantHumanHuman PathologyInstitutionLifeLinkMammalsModelingModificationMolecularMolecular ProfilingMusNatureOther GeneticsOvaryPathway interactionsPatientsPhenotypeProcessResearchResearch PersonnelResourcesSex CharacteristicsSexual DevelopmentSourceTestingTestisUnited States National Institutes of HealthUterusY Chromosomecomputational anatomycongenicexternal genitaliagonad functionimprovedmalemouse modelnovelprotective effectpublic health relevancesexsex determinationsex development disordersry Genestranscription factor
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
In mammals, sex determination is the embryonic process that determines the developmental fate of the bipotential gonad into either testis or ovary. It is triggered by the presence, in males, or the absence in females, of Sry, a Y-linked gene encoding a transcription factor. Disorders of human sex determination cause defects in gonadal function and can result in a spectrum of abnormalities in the internal and external genitalia, ranging from mild sexual ambiguities to complete sex reversal. Although several sex-determining genes have been identified in humans and mouse models, the vast majority of XY patients with disorders of sex determination are not explained genetically, suggesting the existence of other genetic factors involved in this process. In addition, the molecular mechanisms of known sex-determining genes are poorly understood. Our overarching goal is to decipher the molecular events underlying the differentiation of the embryonic gonad, and therefore the process of sex determination. To achieve this objective, we will investigate a mouse model of disorders of sex development. We will identify novel genetic factors protecting against XY sex reversal in the C57BL/6J-YPOS mouse model in which the combination of a Y chromosome originating from a domesticus strain (YPOS) and a C57BL/6J background results in disrupted testicular development. Since our preliminary results show that a congenic region from mouse chromosome 11 protects against sex reversal in the C57BL/6J-YPOS model, we will test the hypothesis that this congenic region carries one or several genes that differ between C57BL/6J and the donor, congenic, fragment and that the difference is responsible for the protection. We will narrow down the congenic region by creating sub-congenic areas and identifying a minimal congenic fragment associated with the protection phenotype (Aim 1). We will also screen for and select candidate genes, investigate their expression profile and their functional relationship with known sex-determining genes and test if the alteration of their expression causes modifications in embryonic gonadal development (Aim 2). Finally, we will investigate the molecular mechanisms of XY sex reversal in the C57BL/6J-YPOS model and analyze the molecular and cellular nature of protective effect from the congenic region on gonadal development (Aim 3). Dissecting the molecular pathway of mammalian sex determination will be crucial in understanding the basic sex differences in gonadal development and the pathophysiology of human disorders of sex development. PUBLIC HEALTH RELEVANCE: One of the most defining moment of our lives is when, in the womb, we embark on a male or female path, and what triggers this moment is when the gene Sry is turned on in males, or stays off in females; yet, many molecular events that happen after Sry action remain poorly understood, and in humans, disruption of sexual development occurs at a frequency of 0.5% to 1%. As only 25% of human pathologies of sex determination are explained genetically, we propose to identify new genes involved in this process by using a mouse model of abnormal sex development. This proposal will elucidate basic questions about how males and females become different, and will improve genetic classification and diagnostic methods of patients born with disorders of sex development.
该子项目是利用该技术的众多研究子项目之一
资源由 NIH/NCRR 资助的中心拨款提供。子项目及
研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金,
因此可以在其他 CRISP 条目中表示。列出的机构是
对于中心来说,它不一定是研究者的机构。
在哺乳动物中,性别决定是胚胎过程,决定双能性腺发育为睾丸或卵巢的命运。它是由男性中存在 Sry 或女性中缺乏 Sry 触发的,Sry 是一种编码转录因子的 Y 连锁基因。人类性别决定障碍会导致性腺功能缺陷,并可能导致内外生殖器一系列异常,从轻微的性别模糊到完全的性别逆转。尽管在人类和小鼠模型中已经鉴定出一些性别决定基因,但绝大多数患有性别决定障碍的 XY 患者无法从遗传学角度进行解释,这表明存在参与这一过程的其他遗传因素。此外,人们对已知性别决定基因的分子机制知之甚少。我们的首要目标是破译胚胎性腺分化的分子事件,从而破译性别决定的过程。为了实现这一目标,我们将研究性发育障碍的小鼠模型。我们将在 C57BL/6J-YPOS 小鼠模型中鉴定出防止 XY 性别逆转的新遗传因素,在该模型中,源自家鼠品系 (YPOS) 的 Y 染色体与 C57BL/6J 背景的组合导致睾丸发育中断。由于我们的初步结果表明,小鼠 11 号染色体的同源区域可以防止 C57BL/6J-YPOS 模型中的性逆转,因此我们将检验这一假设,即该同源区域携带一个或多个与 C57BL/6J 和供体之间不同的基因,同源、片段和差异负责保护。我们将通过创建亚同源区域并识别与保护表型相关的最小同源片段来缩小同源区域的范围(目标 1)。我们还将筛选和选择候选基因,研究它们的表达谱及其与已知性别决定基因的功能关系,并测试它们表达的改变是否会导致胚胎性腺发育的改变(目标2)。最后,我们将研究 C57BL/6J-YPOS 模型中 XY 性别逆转的分子机制,并分析同源区域对性腺发育的保护作用的分子和细胞性质(目标 3)。剖析哺乳动物性别决定的分子途径对于理解性腺发育的基本性别差异和人类性发育障碍的病理生理学至关重要。公共卫生相关性:我们生命中最具决定性的时刻之一是,在子宫里,我们走上了男性或女性的道路,而触发这一时刻的是当 Sry 基因在男性中开启或在女性中关闭时;然而,Sry 作用后发生的许多分子事件仍然知之甚少,在人类中,性发育中断的发生频率为 0.5% 至 1%。由于只有 25% 的人类性别决定病理学可以用基因来解释,我们建议通过使用异常性别发育的小鼠模型来识别参与这一过程的新基因。该提案将阐明男性和女性如何变得不同的基本问题,并将改进出生时性发育障碍患者的遗传分类和诊断方法。
项目成果
期刊论文数量(0)
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Eric J. Vilain其他文献
Eric J. Vilain的其他文献
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{{ truncateString('Eric J. Vilain', 18)}}的其他基金
Role of the Male-Specific Factor Sry in Brain Function
男性特有因素 Sry 在脑功能中的作用
- 批准号:
7911767 - 财政年份:2007
- 资助金额:
$ 0.68万 - 项目类别:
Role of the Male-Specific Factor Sry in Brain Function
男性特有因素 Sry 在脑功能中的作用
- 批准号:
8120981 - 财政年份:2007
- 资助金额:
$ 0.68万 - 项目类别:
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