Mechanisms underlying asymmetric rotation and morphogenesis of the midgut
中肠不对称旋转和形态发生的机制
基本信息
- 批准号:10522575
- 负责人:
- 金额:$ 40万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:ActomyosinAddressAffectAllelesAnisotropyArchitectureBMP4BilateralBirdsBlood VesselsCell PolarityCell physiologyCellsChick EmbryoChickensComputer ModelsCongenital AbnormalityCytoskeletonDataDevelopmentDiagnosisDiagnosticDiseaseDorsalDoseEmbryologyEmbryonic DevelopmentEndothelial CellsEnzymesEquilibriumExtracellular MatrixFailureFeedbackGene ExpressionGene TargetingGenesGeneticGenetic TranscriptionGoalsHandednessHyaluronanIntestinal VolvulusIntestinesIsomerismKnockout MiceLeftLifeLinkLive BirthLocationLymphaticLymphedemaMalignant NeoplasmsMeasurementMechanicsMesenchymalMesenchymeMesenteryMidgutModelingMolecularMorphogenesisMusMuscleMyosin ATPaseNewborn InfantNodalOrganOrganogenesisPatternPhysical condensationProcessPropertyRegulationRieger syndromeRoleRotationShapesSideSignal TransductionStressSuggestionSystemTechnologyTestingTimeTissuesTranslatingTranslationsTubeVascular blood supplyVascularizationVertebratesWorkcell behaviorcell motilitychicken eggclinically significantcraniofacialdosagedriving forcefascinategain of functiongenetic manipulationimprovedlymphatic developmentlymphatic malformationslymphatic vesselmechanical forcemechanotransductionmouse geneticsmouse modelmutantneonatepediatric patientspreventquantitative imagingresponsetoolvasculogenesis
项目摘要
ABSTRACT
The mechanisms discovered through the study of embryogenesis have been fundamental to understanding
disease. We use classic chicken embryology and sophisticated mouse genetics to elucidate how basic cellular
processes define the shape and function of organs. We are most fascinated by left-right (LR) organ asymmetry,
as errors of organ laterality are linked to life-threatening birth defects. The counterclockwise rotation of the gut
is an excellent model to study organ laterality. A critical aspect of this rotation is initiation of a leftward tilt
directed by the master regulator of LR asymmetry, Pitx2. Failure to do so leads to gut malrotation and
catastrophic volvulus in pediatric patients. Whereas rotation forces had long been assumed intrinsic to the gut
tube, we instead discovered that gut rotation is driven by asymmetric deformation of the adjacent dorsal
mesentery (DM) that suspends the gut, and whose cellular architecture is downstream of Pitx2. A key property
of the DM is its exquisite binary organization, with distinct LR compartments that are readily accessible to
genetic manipulation. Cellular and extracellular matrix (ECM) changes in each compartment cause the DM to
deform and tilt the attached gut tube leftward. This critical bias determines gut chirality and frames a model to
explain how LR gene expression is ultimately responsible for changes in cell behavior that initiate asymmetric
organogenesis. The DM is also the sole conduit for blood and lymphatic vessels that serve the gut. We
discovered that Pitx2-dependent mechanisms directing gut tilting are also crucial for patterning the gut
vasculature and provide a mechanism to coordinate these two processes. Whereas most situs-specific
organogenesis depends on Pitx2, mechanistic studies downstream have been hampered by a confounding
“double-right” isomerism in Pitx2 mutants. Whereas Pitx2 expression in all vertebrates is activated by Nodal,
Nodal disappears before asymmetric morphogenesis, leaving unresolved the question of how Pitx2
directs organogenesis. We discovered that Pitx2 expression in the gut is not an extension of previous induction
by Nodal. Instead, we demonstrate that gut rotation requires a “second wave” of Pitx2 that is subject to
mechanoregulation by the latent TGFb, linking LR gene expression to force translation. In aim 1, we determine
the mechanism of Pitx2 dose response during gut, vascular, and lymphatic development and identify two
distinct roles for Pitx2 dependent on its repressive threshold on BMP4 signaling. In aim 2, we define the
molecular mechanism by which the formin Daam2, a Pitx2 target, directs mesenchymal cell polarity, actomyosin
contractile asymmetry, and thereby steers the forces to polarize tilting. In aim 3, we combine cutting-edge physical
measurements of tissue properties with quantitative imaging and computational modeling, to elucidate how
stiffness and force anisotropies drive gut rotation through mechanical feedback. Together, these studies will
significantly advance our understanding of the transcriptional and mechanical control of asymmetric gut and
vascular morphogenesis, a critical step toward improved malrotation diagnostics in newborns.
摘要
通过胚胎发生研究发现的机制一直是理解
疾病。我们使用经典的鸡胚胎学和复杂的小鼠遗传学来阐明基本的细胞
过程定义了器官的形状和功能。我们最着迷的是左右器官的不对称,
因为器官偏侧的错误与危及生命的出生缺陷有关。肠道的逆时针旋转
是研究器官偏侧性的极佳模型。这种旋转的一个关键方面是开始向左倾斜。
由LR不对称的主调节器PITX2指示。如果不这样做,会导致肠道旋转不良和
儿科患者的灾难性扭转。而旋转力长期以来一直被认为是肠道的固有力量
管,相反,我们发现肠道旋转是由邻近背部的不对称变形驱动的
肠系膜(DM),悬挂肠道,其细胞结构位于PITX2下游。一个重要的财产
DM的特点是其精致的二进制组织,具有独特的LR隔间,易于访问
基因操纵。细胞和细胞外基质(ECM)在每个隔室的变化导致DM
将连接的肠管向左变形和倾斜。这一关键偏差决定了肠道手性,并将模型构建为
解释LR基因的表达如何最终导致引发不对称的细胞行为变化
器官发生。糖尿病也是供应肠道的血液和淋巴管的唯一管道。我们
发现依赖Pitx2的机制引导肠道倾斜对肠道模式也是至关重要的
血管系统,并提供一种机制来协调这两个过程。而大多数站点特定的
器官发生依赖于PITX2,下游的机制研究因一种令人困惑的
Pitx2突变体的“双右”异构性。虽然所有脊椎动物中的Pitx2表达都是由Nodal激活的,
结节在不对称形态发生之前就消失了,留下了一个悬而未决的问题,即Pitx2如何
引导器官发生。我们发现,Pitx2在肠道中的表达不是先前诱导的延伸
由诺达尔。相反,我们证明肠道旋转需要Pitx2的“第二波”,它受制于
通过潜在的TGFb进行机械调节,将LR基因的表达与强制翻译联系在一起。在目标1中,我们确定
肠、血管和淋巴发育过程中Pitx2的剂量反应机制及鉴定
Pitx2的不同作用取决于其对BMP4信号的抑制阈值。在目标2中,我们定义了
作为PITX2靶标的Forin Daam2引导间充质细胞极性肌动球蛋白的分子机制
收缩不对称,从而引导力量极化倾斜。在目标3中,我们结合了尖端的物理
用定量成像和计算模型测量组织特性,以阐明如何
刚度和力的各向异性通过机械反馈驱动肠道旋转。总而言之,这些研究将
极大地促进了我们对不对称肠道的转录和机械控制的理解
血管形态发生,改善新生儿旋转不良诊断的关键一步。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Natasza A Kurpios其他文献
Natasza A Kurpios的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Natasza A Kurpios', 18)}}的其他基金
Gut-specific lymphatic patterns and progenitor heterogeneity during intestinal health and disease
肠道健康和疾病期间肠道特异性淋巴模式和祖细胞异质性
- 批准号:
9311038 - 财政年份:2017
- 资助金额:
$ 40万 - 项目类别:
Gut-specific lymphatic patterns and progenitor heterogeneity during intestinal health and disease
肠道健康和疾病期间肠道特异性淋巴模式和祖细胞异质性
- 批准号:
9919553 - 财政年份:2017
- 资助金额:
$ 40万 - 项目类别:
Mechanisms underlying asymmetric rotation and vascular development of the midgut
中肠不对称旋转和血管发育的机制
- 批准号:
8434804 - 财政年份:2012
- 资助金额:
$ 40万 - 项目类别:
Mechanisms underlying asymmetric rotation and vascular development of the midgut
中肠不对称旋转和血管发育的机制
- 批准号:
8297300 - 财政年份:2012
- 资助金额:
$ 40万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 40万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 40万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 40万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 40万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 40万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 40万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 40万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 40万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 40万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 40万 - 项目类别:
Research Grant