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

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
{{ 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 }}

Mary Catherine Wallingford其他文献

Mary Catherine Wallingford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 }}

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了