Regulation of Cellular Zn Redistribution: A Role of ZnT2

细胞锌重新分布的调节：ZnT2 的作用

• 批准号: 7849656
• 负责人: SHANNON L KELLEHER
• 金额: $ 34.99万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849656
• 关键词: Animals; Behavioral; Biological; Cell membrane; Cell model; Cell physiology; Cells; Contracts; Cues; Development; Discipline of Nursing; Disease; Epithelial Cells; Functional disorder; Generations; Genes; Genomics; Goals; Health; Hormonal; Hormones; Human; In Vitro; Infant; Knockout Mice; Lactation; Malignant neoplasm of prostate; Mammary gland; Metabolism; Milk; Mitochondria; Morbidity - disease rate; Mutation; Neonatal; Neurons; Outcome; Phase; Phenotype; Physiological; Physiological Processes; Play; Process; Prolactin; Proliferating; Prostate; Protein Isoforms; Proteomics; Public Health; Regulation; Role; Secretory Vesicles; Specificity; System; Testing; Tissues; Transgenic Organisms; Variant; Vesicle; Work; Zinc; Zinc deficiency; cell growth regulation; immune function; improved; in vivo; malignant breast neoplasm; mortality; mouse model; outcome forecast; public health relevance; reproductive function; response; sperm cell; tumor progression; uptake; zinc-binding protein

DESCRIPTION (provided by applicant): The long-term goal of this application aims to determine how tissues with extraordinary zinc (Zn) requirements, such as mammary gland and prostate, redistribute cellular Zn pools during secretion. Impaired Zn secretion from the mammary gland during lactation results in severe neonatal Zn deficiency. This compromises neuronal and behavioral development, impairs immune function, and increases infant morbidity and/or mortality. Aberrant Zn transport is also implicated in breast cancer. Dysfunctional prostate Zn transport impairs sperm viability and is associated with prostate cancer. These observations underscore the need to understand Zn transport mechanisms in these highly specialized tissues. Zinc transporter-2 (ZnT2) expression is restricted to tissues such as mammary gland and prostate. A mutation in ZnT2 reduces Zn secretion into milk in humans and ZnT2-suppression in mammary epithelial cells reduces Zn secretion in vitro. Discrete ZnT2 isoforms have been identified which are associated with mitochondria (mZnT2) and intracellular vesicles (sZnT2) in mammary epithelial cells. Mitochondrial Zn uptake and Zn concentration parallels mZnT2 abundance, while Zn secretion parallels sZnT2 abundance. Similar to observations in prostate cells, the hormone prolactin shifts Zn distribution in mammary epithelial cells. Prolactin contracts mitochondrial Zn pools while concurrently increasing Zn transport. This redistribution is associated with decreased mZnT2 and increased sZnT2 abundance. We hypothesize that prolactin regulates discrete ZnT2 isoforms to redistribute cellular Zn pools from mitochondria to secretory vesicles to facilitate extraordinary Zn secretion in highly specialized secretory tissues. We propose to use the mammary gland as a representative system to explore potential mechanisms responsible for cellular Zn redistribution using animal and cell models. The four specific aims of this application are to, (1) determine if mitochondrial ZnT2 facilitates expansion of a mitochondrial Zn pool using genomic and proteomic approaches; (2) determine mechanisms by which prolactin redistributes cellular Zn pools through changes in sZnT2 during secretion; (3) develop a transgenic mammary gland mouse model to determine if cellular Zn pools are redistributed by mZnT2 and sZnT2 in vivo; (4) develop a ZnT2-null mouse model to document the biological significance ZnT2 and determine if other Zn transporters participate in Zn pool redistribution in mammary gland and prostate in vivo. Taken together, these studies will identify specific mechanisms which regulate cellular Zn redistribution in highly specialized tissues and are crucial to our understanding of cellular function, Zn metabolism and human health and disease. The mammary and prostate glands are highly specialized secretory tissues that are responsible for extraordinary Zn secretion. Impaired Zn secretion from the mammary gland during lactation results in severe neonatal Zn deficiency which compromises neuronal and behavioral development, impairs immune function, and increases infant morbidity and/or mortality. Aberrant Zn transport is also implicated in breast cancer. Dysfunctional Zn transport in prostate has been implicated in prostate cancer, sperm viability and impaired reproductive function. These observations underscore the need to understand Zn transport mechanisms in these unique tissues. Thus, this application has significance for improving public health outcomes and advancing our understanding of basic cellular mechanisms. PUBLIC HEALTH RELEVANCE: The mammary and prostate glands are highly specialized secretory tissues that are responsible for extraordinary Zn secretion. Impaired Zn secretion from the mammary gland during lactation results in severe neonatal Zn deficiency which compromises neuronal and behavioral development, impairs immune function, and increases infant morbidity and/or mortality. Aberrant Zn transport is also implicated in breast cancer. Dysfunctional Zn transport in prostate has been implicated in prostate cancer, sperm viability and impaired reproductive function. These observations underscore the need to understand Zn transport mechanisms in these unique tissues. Thus, this application has significance for improving public health outcomes and advancing our understanding of basic cellular mechanisms.

描述（由申请人提供）：本申请的长期目标旨在确定具有特殊锌（Zn）需求的组织，如乳腺和前列腺，在分泌过程中如何重新分配细胞锌池。哺乳期乳腺锌分泌受损导致新生儿严重缺锌。这会损害神经元和行为发育，损害免疫功能，并增加婴儿发病率和/或死亡率。锌转运异常也与乳腺癌有关。前列腺锌转运功能障碍损害精子活力并与前列腺癌有关。这些观察结果强调了了解锌在这些高度特化组织中的转运机制的必要性。锌转运蛋白-2 （ZnT2）的表达仅限于乳腺和前列腺等组织。ZnT2突变可减少人乳中锌的分泌，乳腺上皮细胞抑制ZnT2可减少体外锌的分泌。已经鉴定出与乳腺上皮细胞线粒体（mZnT2）和细胞内囊泡（sZnT2）相关的离散ZnT2亚型。线粒体锌摄取和锌浓度与mZnT2丰度相似，而锌分泌与sZnT2丰度相似。与在前列腺细胞中的观察结果相似，催乳素改变了锌在乳腺上皮细胞中的分布。催乳素收缩线粒体锌库，同时增加锌转运。这种再分配与mZnT2的减少和sZnT2丰度的增加有关。我们假设催乳素调节离散的ZnT2亚型，将细胞锌池从线粒体重新分配到分泌囊泡，以促进高度特化的分泌组织中非凡的锌分泌。我们建议使用乳腺作为代表性系统，利用动物和细胞模型来探索细胞锌再分配的潜在机制。该应用程序的四个具体目标是：(1)使用基因组学和蛋白质组学方法确定线粒体ZnT2是否有助于线粒体Zn库的扩展；(2)通过分泌过程中sZnT2的变化确定催乳素重新分配细胞锌池的机制；(3)建立转基因乳腺小鼠模型，确定体内细胞锌池是否被mZnT2和sZnT2重新分配；(4)建立ZnT2缺失小鼠模型，验证ZnT2的生物学意义，并确定体内是否有其他锌转运体参与乳腺和前列腺锌池的再分配。综上所述，这些研究将确定在高度特化的组织中调节细胞锌再分配的特定机制，对我们理解细胞功能、锌代谢和人类健康和疾病至关重要。乳腺和前列腺是高度特化的分泌组织，负责非凡的锌分泌。哺乳期乳腺锌分泌受损导致新生儿严重缺锌，损害神经元和行为发育，损害免疫功能，并增加婴儿发病率和/或死亡率。锌转运异常也与乳腺癌有关。锌在前列腺中的转运功能失调与前列腺癌、精子活力和生殖功能受损有关。这些观察结果强调了了解锌在这些独特组织中的转运机制的必要性。因此，这一应用对改善公共卫生结果和促进我们对基本细胞机制的理解具有重要意义。公共卫生相关性：乳腺和前列腺是高度特化的分泌组织，负责大量的锌分泌。哺乳期乳腺锌分泌受损导致新生儿严重缺锌，损害神经元和行为发育，损害免疫功能，并增加婴儿发病率和/或死亡率。锌转运异常也与乳腺癌有关。锌在前列腺中的转运功能失调与前列腺癌、精子活力和生殖功能受损有关。这些观察结果强调了了解锌在这些独特组织中的转运机制的必要性。因此，这一应用对改善公共卫生结果和促进我们对基本细胞机制的理解具有重要意义。