Gut-specific lymphatic patterns and progenitor heterogeneity during intestinal health and disease
Gut-specific lymphatic patterns and progenitor heterogeneity during intestinal health and disease
批准号:
9311038
负责人:
Natasza A Kurpios
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
项目状态:
已结题
起止时间:
2017-05-01 至 2022-04-30
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
中文摘要
摘要
胚胎中肠必须以一种复杂而刻板的模式旋转,以呈现熟悉的位置
在体腔内。 这一过程的失败会导致旋转不良和灾难性的中肠
肠扭转,即肠和相关脉管系统的绞窄。 我们的研究已经建立了高度
保守的分子机制,通过这些机制实现肠道的机械旋转,
保守的对称性破坏转录因子Pitx 2。 最近,我们发现,
器官不对称机制形成了复杂的血管和淋巴管网络,
排出脊椎动物的肠道 因此,有了一个核心分子库,发育中的肠道就可以在早期
结构、分子和血管的不对称性决定了成人器官的形式和功能。 在
背肠系膜是将肠道悬挂在体腔内的中胚层组织桥,
供应未来肠道的动脉和血管出现在Pitx 2-β-Cxcl 12信号通路的下游,
它指导Cxcr 4-β-阳性成血管细胞逐渐组装成内皮索,
船舶.我们已经证明,Pitx 2、Cxcr 4或Cxcl 12功能的缺失会破坏动脉和淋巴管的形成,
特别是在肠道中,并靶向一种新的淋巴前体群体,
来源于肠系膜淋巴囊。 肠道代谢物在膳食脂质的吸收中起着至关重要的作用,
这一功能将它们与体内所有其他淋巴网络分开。虽然我们的数据显示,
动脉网的最终形成取决于动脉网的预先组装,
这种关系的机制尚不清楚。在我们的第一个目标,我们解决的具体作用和时机,
Pitx 2在淋巴模式和生理学中的表达。 使用Pitx 2突变小鼠系,我们将
将最早的胚胎偏侧性通路与淋巴管系统的器官内固有模式联系起来,
内脏在我们的第二个目标中,我们在小鼠肠道中测试Pitx 2和Vegf-β-C之间的关系,并利用
鸡胚的可及性。 在我们的第三个目标中,我们将消融动脉、淋巴或
使用他莫昔芬诱导的Cre的Cx40-CRE、Prox 1-CRE和Tie 2-CRE驱动剂的广义内皮。我们将测试
使用Cxcr 7突变体,Cxc 112第二受体Cxcr 7补偿Cxcr 4损失的能力,
报告小鼠。 从这些实验中吸取的教训将改变我们思考和研究的方式
哺乳动物肠道的代谢,并将揭示新的潜在目标,当地代谢,
肠道疾病
英文摘要
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.
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会议论文
Gut-specific lymphatic patterns and progenitor heterogeneity during intestinal health and disease
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批准号:9919553
-
项目类别:
-
资助金额:$39.25万
-
财政年份:2017
-
负责人:Natasza A Kurpios
-
依托单位:
Mechanisms underlying asymmetric rotation and vascular development of the midgut
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批准号:8434804
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项目类别:
-
资助金额:$32.14万
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财政年份:2012
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负责人:Natasza A Kurpios
-
依托单位:
Mechanisms underlying asymmetric rotation and vascular development of the midgut
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批准号:8297300
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项目类别:
-
资助金额:$33.11万
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财政年份:2012
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负责人:Natasza A Kurpios
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依托单位:
Mechanisms underlying asymmetric rotation and morphogenesis of the midgut
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批准号:10522575
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项目类别:
-
资助金额:$40.0万
-
财政年份:2012
-
负责人:Natasza A Kurpios
-
依托单位:
海外基金