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
基本信息
- 批准号:9311038
- 负责人:
- 金额:$ 38.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAngioblastAortaArteriesBindingBiological AssayBloodBlood VesselsBody cavitiesCXCR4 ReceptorsChIP-seqChickensChyleComplexDataDefectDepositionDevelopmentDietary FatsDiseaseDorsalDoseEmbryoEndotheliumExtravasationFailureFutureG-Protein-Coupled ReceptorsGene ExpressionGeneticGoalsHandednessHealthHeterogeneityImageImpairmentIntestinal VolvulusIntestinesLaboratoriesLeftLegal patentLesionLigandsLightLinkLipidsLiverLymphLymphangiogenesisLymphaticLymphatic Endothelial CellsLymphatic EndotheliumLymphatic vesselMaintenanceMechanicsMesenteryMetabolic DiseasesMidgutMolecularMusMuscleMutant Strains MiceOrganOutcomePathogenesisPathway interactionsPatternPhenotypePhysiologyPlayPopulationPositioning AttributeProcessReporterResearchResolutionRoleRotationSideSignal PathwaySignal TransductionSmooth MuscleStructureTamoxifenTechnologyTestingTexasTissuesVascular Endothelial Growth FactorsVeinsVenousWeight Gainabsorptionbody cavitycell typedisease phenotypeeggexperimental studyinnovationlipid transportmorphogensmouse modelmutantnovelnovel therapeuticsprecursor cellprogenitorpupreceptorsucklingtooltranscription factor
项目摘要
ABSTRACT
The embryonic midgut must rotate in a complex yet stereotypical pattern to assume the familiar positioning
within the body cavity. Failure of this process causes malrotation and predisposes to catastrophic midgut
volvulus, a strangulation of the gut and associated vasculature. Our research has established the highly
conserved molecular mechanisms by which the mechanical rotation of the gut is achieved, orchestrated by
the conserved symmetry breaking transcription factor Pitx2. More recently we have shown that the same
organ asymmetry mechanisms pattern the complex network of blood and lymphatic vessels that supply and
drain the vertebrate gut. Thus with one core molecular repertoire, the developing gut assumes early
structural, molecular and vascular asymmetries that determine the form and function of the adult organ. In
the dorsal mesentery, a bridge of mesodermal tissue that suspends the gut within the body cavity, the
arteries and lymphatics that supply the future gut arise downstream of a Pitx2-‐‑Cxcl12 signaling pathway,
which directs the progressive assembly of Cxcr4-‐‑positive angioblasts into endothelial cords and patent
vessels. We have shown that loss of Pitx2, Cxcr4 or Cxcl12 function disrupts artery and lymphatic formation
specifically in the gut, and targets a novel population of lymphatic precursors that is distinct from those
derived from mesenteric lymph sac. Gut lymphatics have a crucial role in absorption of dietary lipids, a
function that separates them from all other lymphatic networks in the body. While our data highlight that the
eventual formation of lymphatics depends on the prior assembly of the arterial network, the specific
mechanisms of this relationship remain unclear. In our first aim, we address the specific roles and timing of
Pitx2 expression during lymphatic patterning and physiology. Using Pitx2 mutant mouse lines, we will
connect the earliest embryonic laterality pathways with organ-‐‑intrinsic patterns of lymphatic vasculature in
the gut. In our second aim, we test the relationship between Pitx2 and Vegf-‐‑C in the mouse gut and utilizing
the accessibility of chicken embryo. In our third aim, we will ablate Cxcr4 in arterial, lymphatic or
generalized endothelium using Cx40-‐‑, Prox1-‐‑ and Tie2-‐‑CRE drivers of tamoxifen-‐‑inducible Cre. We will test
the ability of Cxcr7, a second receptor for Cxcl12, to compensate for Cxcr4 loss using Cxcr7 mutant and
reporter mice. Lessons learned from these experiments will change the way we consider and study
lymphatics of the mammalian intestine, and will shed new light on potential targets of local lymphatics in
diseases of the gut.
摘要:
新的胚胎中肠必须在一个非常复杂但又刻板的模式中旋转,才能承担最熟悉的角色定位。
在身体内部有空洞。这一过程的失败可能会导致旋转不良,并容易导致灾难性的中肠。
肠扭转是一种常见的肠道绞窄性疾病,与血管系统相关。我们的研究团队已经建立了很高的基础。
通过保守的分子机制来实现肠道功能的机械化和旋转化,并由生物来协调。
我们通过破坏转录因子Pitx2来保持对称性。最近,我们已经证明了这一点是相同的。
器官功能不对称的机制和模式是由血液和淋巴管组成的复杂的营养网络,它影响着供应和营养。
排干脊椎动物的肠道。因此,只有一个核心的分子谱系,就像发育中的肠道很早就假定的那样。
结构、分子结构和血管结构的不对称性将决定人类成体器官的形态和功能。
背侧肠系膜是中胚层组织的重要桥梁,它将肠道组织悬挂在体腔内。
动脉和淋巴管认为,未来肠道的供应可能出现在Pitx2-CXCL12信号通路的下游。
该公司指导了CXCR4-阳性血管母细胞进入血管内皮细胞的最先进的血管组装过程,并获得了专利。
血管。我们已经证明,Pitx2、CXCR4或CXCL12功能的丧失会扰乱动脉和淋巴管的形成。
具体地说,他们的肠道、血液和血液目标是一种全新的淋巴管前体细胞群体,这与其他人截然不同。
从肠系膜和淋巴囊中提取的脂肪。肠道和淋巴管在饮食脂质的吸收中起着至关重要的作用。
将它们与该机构中的所有其他淋巴系统网络分开的功能。同时,我们的数据也强调了这一点。
淋巴管的最终形成取决于动脉和淋巴管网络之前的组装过程,以及具体的过程。
建立这种关系的机制尚不清楚。为了实现我们的首要目标,我们将解决这一关系的具体作用和时机选择问题。
Pitx2在淋巴组织构型和生理过程中的表达。通过使用Pitx2突变体和小鼠品系,我们将发现。
将最早的胚胎侧化和通路与器官-淋巴管和血管系统的内在模式--联系起来。
肠道。在我们的第二个目标中,我们将在小鼠的肠道移植和利用中测试Pitx2基因和血管内皮生长因子-C基因之间的关系。
鸡胚胎的可及性。为了实现我们的第三个目标,我们将在动脉、淋巴管或淋巴管中切除CXCR4基因。
使用Cx40-,Prox1-1和Tie2-Cre作为他莫昔芬-Cre的驱动程序。-Cre的诱导。我们将继续测试。
CXCR7是CXCL12的第二个受体,它的能力是通过使用CXCR7的突变株和突变体来补偿CXCR4的损失。
记者问老鼠。从这些实验中吸取的教训将改变我们思考和学习的方式。
主要哺乳动物肠道、脾和肺的淋巴学研究将为中国地方淋巴管研究的潜在靶点提供新的线索。
疾病包括肠道疾病。
项目成果
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{{ 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:
9919553 - 财政年份:2017
- 资助金额:
$ 38.96万 - 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:
$ 38.96万 - 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:
$ 38.96万 - 项目类别:
Mechanisms underlying asymmetric rotation and morphogenesis of the midgut
中肠不对称旋转和形态发生的机制
- 批准号:
10522575 - 财政年份:2012
- 资助金额:
$ 38.96万 - 项目类别:
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