Determination of maternal-fetal phosphate transport mechanisms and the role of sodium-dependent phosphate transporters in extraembryonic tissues
确定母胎磷酸盐转运机制以及钠依赖性磷酸盐转运蛋白在胚胎外组织中的作用
基本信息
- 批准号:9895837
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-18 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectApicalArteriesBasement membraneBiologicalBiological MarkersBiologyBiomedical ResearchBloodBlood VesselsBlood capillariesBone DensityBrain PathologyCalciumCaliberCell Membrane StructuresCellsCessation of lifeCharacteristicsChildhoodChorionic villiClinical ResearchComplexDNADataDefectDepositionDevelopmentDevelopmental ProcessDiagnosisEmbryoEndocrineEndocytosisEtiologyEventFamilyFetal Growth RetardationFunctional disorderGestational AgeGoalsGrowth and Development functionHealthHealth Care CostsHealth SciencesHumanHuman DevelopmentHypertensionHypoxiaImpairmentInorganic Phosphate TransporterInstitutesInvadedKidney DiseasesKnockout MiceLeadLifeLinkMaternal MortalityMediatingMedical Care CostsMentorsMetabolismMineralsModelingMolecularMorphologyMothersMusNutrientOrganOxidative PhosphorylationPTH genePathway interactionsPerinatal mortality demographicsPeriodicityPhasePhenotypePhosphorusPlacentaPlacenta DiseasesPlacentationPlayPre-EclampsiaPregnancyPremature BirthPreventionProcessProteinsProteinuriaPublic HealthPublishingReperfusion TherapyResearchResearch Project GrantsRodentRoleScienceSerumSignal TransductionSodiumSpiral Artery of the EndometriumSyncytiotrophoblastSyndromeTestingTimeTissuesTrainingTremorUrineUterusVascular DiseasesVascular remodelingWorkYangYolk Sacangiogenesisblood vessel developmentbonecalcificationcardiovascular disorder riskclinically significantdevelopmental diseasediagnostic biomarkerearly onseteditorialextracellularfetalfetal bloodfetus cellglobal healthimmunoregulationimprovedinorganic phosphateinsightloss of functionmaternal morbiditymortalitymouse modelneonatal deathoffspringperinatal morbiditypregnancy disorderpreventprogramstooltrophoblastuptakevascular abnormalitywasting
项目摘要
Project Summary: I aim to establish a biomedical research lab that investigates mechanisms of placental
development and pathophysiology. Dr. Alan Guttmacher recently identified the placenta as “the least
understood human organ” when discussing the Human Placenta Project, a new initiative of the National
Institute of Childhood Health and Human Development (Kaiser J. 2014. Science 344(6188):1073).
Placental dysfunction and resulting syndromes are poorly understood despite the clear significance to
human health. Impaired placental function can lead to fetal growth restriction and is linked to preeclampsia,
a pregnancy specific life-threatening hypertensive syndrome within unknown etiology. Preeclampsia is a
leading cause of maternal and neonatal death. It occurs in 3-8% of pregnancies, and ~4% of these cases
result in mortality. Other cases lead to premature birth, developmental disorders in offspring, increased risk
for cardiovascular and kidney diseases later in life for mothers, and substantial health care costs.
Unfortunately, the number of preeclampsia cases is increasing. Stephen Hodgins, Deputy-in-Chief of
Global Health: Science and Practice, recently published an editorial titled “Pre-eclampsia as an Underlying
Cause for Perinatal Deaths: Time for Action” (Hodgins S. 2015. GHSP; 3(4):525-527), highlighting this
important global public health issue. A better understanding of the placenta is greatly needed in order to
diagnose, treat, and prevent preeclampsia and other health issues resulting from placental dysfunction.
My work will address several key unknowns in placental development and pathophysiology. I will begin by
determining molecular mechanisms of maternal-fetal phosphate transport. Phosphorus is an essential
nutrient and it is required for several processes in growth and development, such as DNA and cell
membrane structure, bone deposition, oxidative phosphorylation, and others. Remarkably, the molecular
mechanisms and proteins that regulate maternal-fetal phosphate transport remain unknown. I have
identified a likely family of maternal-fetal phosphate transporters and developed loss of function mouse
models that revealed specific developmental requirements. PiT-1 loss results in embryonic lethality,
decreased endocytosis, and impaired angiogenesis (Wallingford et al. 2014. Mech. Dev. 133:189-202).
PiT-2 deficiency results in fetal growth restriction, decreased bone density, and abundant placental
calcification (Wallingford et al. Reprod. Biol. and Wallingford et al. Brain Pathology – both in process). The
PiT-2 null mouse is the first and only placental calcification model available. My data suggests that PiT-2
mediated anti-calcific mechanisms may play a key role in preventing placental dysfunction, and clinical
studies have indeed correlated altered expression levels of PiT-1 and PiT-2 with preeclampsia (Yang et al.
2014. Mol. Reprod. & Dev. 81:851-860). Further, calcification of the placenta is frequently observed in
humans, and I have identified distinct types of placental calcification that vary between pregnancy types.
I have developed models of how loss or dysfunction of Slc20a1 and Slc20a2 could lead to preeclampsia;
here I propose aims that will test these models in mouse and human and provide fundamental mechanistic
insights into phosphate transporter biology and placental pathophysiology. As a postdoctoral trainee
during the mentored (K99) phase of the research program, I will build upon my preliminary data and
obtain the training necessary to test the hypothesis that placental dysfunction and preeclampsia can be
caused by dysregulated phosphate metabolism that disrupts placental development and function, and
promotes the deposition of placental calcification. I will test my prosed models of Slc20a1 and Slc20a2 yolk
sac and placental phosphate transport, and publish these findings during the K99 phase. After I have
transitioned into the independent (R00) phase, I will continue to investigate molecular mechanisms of
Slc20a1 and Slc20a2 function. I will also test hypotheses aimed at determining how loss of Slc20a1 and
Slc20a2 could lead to placental dysfunction, how calcification impacts placental function, and whether
candidate pro-calcific markers are diagnostic tools for placental calcification-associated preeclampsia.
Project Summary: I aim to establish a biomedical research lab that investigates mechanisms of placental
development and pathophysiology. Dr. Alan Guttmacher recently identified the placenta as “the least
understood human organ” when discussing the Human Placenta Project, a new initiative of the National
Institute of Childhood Health and Human Development (Kaiser J. 2014. Science 344(6188):1073).
Placental dysfunction and resulting syndromes are poorly understood despite the clear significance to
human health. Impaired placental function can lead to fetal growth restriction and is linked to preeclampsia,
a pregnancy specific life-threatening hypertensive syndrome within unknown etiology. Preeclampsia is a
leading cause of maternal and neonatal death. It occurs in 3-8% of pregnancies, and ~4% of these cases
result in mortality. Other cases lead to premature birth, developmental disorders in offspring, increased risk
for cardiovascular and kidney diseases later in life for mothers, and substantial health care costs.
Unfortunately, the number of preeclampsia cases is increasing. Stephen Hodgins, Deputy-in-Chief of
Global Health: Science and Practice, recently published an editorial titled “Pre-eclampsia as an Underlying
Cause for Perinatal Deaths: Time for Action” (Hodgins S. 2015. GHSP; 3(4):525-527), highlighting this
important global public health issue. A better understanding of the placenta is greatly needed in order to
diagnose, treat, and prevent preeclampsia and other health issues resulting from placental dysfunction.
My work will address several key unknowns in placental development and pathophysiology. I will begin by
determining molecular mechanisms of maternal-fetal phosphate transport. Phosphorus is an essential
nutrient and it is required for several processes in growth and development, such as DNA and cell
membrane structure, bone deposition, oxidative phosphorylation, and others. Remarkably, the molecular
mechanisms and proteins that regulate maternal-fetal phosphate transport remain unknown. I have
identified a likely family of maternal-fetal phosphate transporters and developed loss of function mouse
models that revealed specific developmental requirements. PiT-1 loss results in embryonic lethality,
decreased endocytosis, and impaired angiogenesis (Wallingford et al. 2014. Mech. Dev. 133:189-202).
PiT-2 deficiency results in fetal growth restriction, decreased bone density, and abundant placental
calcification (Wallingford et al. Reprod. Biol. and Wallingford et al. Brain Pathology – both in process). The
PiT-2 null mouse is the first and only placental calcification model available. My data suggests that PiT-2
mediated anti-calcific mechanisms may play a key role in preventing placental dysfunction, and clinical
studies have indeed correlated altered expression levels of PiT-1 and PiT-2 with preeclampsia (Yang et al.
2014. Mol. Reprod. & Dev. 81:851-860). Further, calcification of the placenta is frequently observed in
humans, and I have identified distinct types of placental calcification that vary between pregnancy types.
I have developed models of how loss or dysfunction of Slc20a1 and Slc20a2 could lead to preeclampsia;
here I propose aims that will test these models in mouse and human and provide fundamental mechanistic
insights into phosphate transporter biology and placental pathophysiology. As a postdoctoral trainee
during the mentored (K99) phase of the research program, I will build upon my preliminary data and
obtain the training necessary to test the hypothesis that placental dysfunction and preeclampsia can be
caused by dysregulated phosphate metabolism that disrupts placental development and function, and
promotes the deposition of placental calcification. I will test my prosed models of Slc20a1 and Slc20a2 yolk
sac and placental phosphate transport, and publish these findings during the K99 phase. After I have
transitioned into the independent (R00) phase, I will continue to investigate molecular mechanisms of
Slc20a1 and Slc20a2 function. I will also test hypotheses aimed at determining how loss of Slc20a1 and
Slc20a2 could lead to placental dysfunction, how calcification impacts placental function, and whether
candidate pro-calcific markers are diagnostic tools for placental calcification-associated preeclampsia.
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cellular Complexity of Hemochorial Placenta: Stem Cell Populations, Insights from scRNA-seq, and SARS-CoV-2 Susceptibility.
- DOI:10.1007/s40778-021-00194-6
- 发表时间:2021
- 期刊:
- 影响因子:1.4
- 作者:Mallery CS Jr;Carrillo M;Mei A;Correia-Branco A;Kashpur O;Wallingford MC
- 通讯作者:Wallingford MC
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