Iron Delivery in the Developing Kidney

说明(申请人提供)：孕期缺铁是世界上最常见的微量营养素缺乏症，影响多达20亿人。孕期缺铁会增加胚胎死亡、早产和低出生体重婴儿的风险，这突出了了解所需的铁量是如何输送到胚胎以预防出生缺陷的重要性。发育中的肾脏需要足够的铁，才能在怀孕期间和出生后早期实现最佳的器官形成。铁在整个肾脏形态发生过程中都是必需的，包括后肾间充质向上皮细胞的转化、输尿管芽的分枝和出生后肾小球形成的完成。缺铁会减少肾单位的数量，导致发育不全和高血压，这会增加成年后发生肾功能衰竭和心血管疾病的风险。然而，铁从胎盘运输到包括肾脏在内的发育器官中不同细胞系的机制一直是一个黑匣子，因此在了解缺铁对器官发生的影响方面进展甚微，几乎没有文献报道。目前的铁交易模式源于对成人的研究。这些研究揭示了所谓的铁循环背后的分子机制，但令人惊讶的是，其主要成分(Transfer，Transfer Receptor1[Tfr1]，二价金属转运蛋白1[DMT1]，Steap3，Tim)的缺失在胚胎中产生的表型比这些蛋白的普遍存在和物种间的保守所预测的要有限得多。因此，目前尚不清楚发育中的肾脏中的输尿管芽和间充质是否从不同的来源获得铁，铁的输送是否是“细胞自主”的，或者相互诱导是否也包括间隔间的铁交换，以及缺铁是否以不同的方式失调不同细胞系的器官发生？在这项建议中，我们通过对发育中的肾脏中心铁传递途径Tf-Tfr1的功能进行基因解剖，确定了诱导真正生长和发育的铁运输过程。最初的数据出人意料地提出了以下假设，我们在这里测试：这些假设是(1)细胞特异性的，(2)对Tf-Tfr1的时间特异性要求，(3)Tfr1介导的经典细胞自主机制，但另外还有一种细胞非自主途径的可能性，(4)非Tf铁供体的活动，包括一条涉及铁蛋白的新途径，以及(5)一种独特的铁转运体的活性，它充分且必要地将Tf铁转移到发育中的肾脏的细胞液中。这些假说识别和测试了新的、组织特异性的和阶段特异性的铁输送机制，暗示了复杂和高度调控的机制使细胞需求与铁捕获同步。我们认为，这些途径很可能是妊娠期缺铁的目标，而妊娠期缺铁会限制肾脏的生长和发育。

DESCRIPTION (provided by applicant): Iron deficiency in pregnancy is the most common micronutrient deficiency in the world, affecting as many as 2 billion people. Iron deficiency in pregnancy increases the risk for embryonic mortality, a preterm delivery and low birth weight baby, which highlights the importance of understanding how the required quantity of iron is delivered to the embryo for the prevention of birth defects. The developing kidney requires sufficient iron for optimal organogenesis during pregnancy and in the early postnatal period. Iron is required throughout kidney morphogenesis, including during conversion of the metanephric mesenchyme into epithelia, during the branching of the ureteric bud, and during the postnatal completion of glomerulogenesis. Iron deficiency reduces nephron number and results in hypoplasia and hypertension, which increases the risk of renal failure and cardiovascular diseases in adult life. However, the mechanism by which iron traffics from the placenta to different cell lineages in developing organs including kidney has been a "black box" and as a result there have been few advances and almost no literature in understanding the impact of iron deficiency on organogenesis. The current paradigm of iron trafficking derives from studies in the adult. These studies have revealed the molecular mechanisms underlying the so-called iron cycle, but surprisingly the deletion of its main components (transferring, transferring receptor1[Tfr1], divalent metal transporter 1[DMT1], Steap3, TIM) has produced much more limited phenotypes in the embryos than might have been predicted by the ubiquity of these proteins, and their conservation among species. Hence it remains unclear whether the ureteric bud and mesenchyme in the developing kidney obtain iron from different sources, whether iron delivery is "cell autonomous" or does reciprocal induction also include the exchange of iron between compartments, and whether iron deficiency dysregulates organogenesis of different cell lineages differently? In this proposal, we identify iron trafficking processes that induce real growth and development by genetically dissecting the functions of the central iron delivery pathway, Tf-Tfr1, in the developing kidney. The initial data unexpectedly suggested the following hypotheses, which we test here: these are (1) a cell specific, and (2) a temporally specific requirement for Tf-Tfr1, (3) a classical cell autonomous mechanism mediated by Tfr1, but additionally the possibility of a cell non-autonomous pathway as well, (4) the activity of non-Tf iron donors, including a novel pathway involving ferritin and (5) the activity of a unique iron transporter that is both sufficient and necessary to transfer Tf iron to the cytosol of the developing kidney. These hypotheses identify and test novel, tissue specific, and stage specific mechanisms of iron delivery, implicating that complex and highly regulated mechanisms synchronize cell need with iron capture. We suggest that these pathways are likely to be the target of iron deficiency in pregnancy, which is known to limit kidney growth and development.