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.
文摘
项目成果
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Natasza A Kurpios其他文献
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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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