Identification of the genetic mechanisms governing mammalian nephron endowment

鉴定控制哺乳动物肾单位禀赋的遗传机制

• 批准号: 10247020
• 负责人: Alison Jarmas
• 金额: $ 5.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2023-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247020
• 关键词: Address; Algorithms; Biological Assay; Cells; Childhood; Chromosomes; Chronic Kidney Failure; Clinical; Complement; Data; Development; Diagnostic; Embryo; Endowment; Environment; Epithelial; Equilibrium; Exhibits; Fellowship; Filtration; Fostering; Gene Expression Profile; Generations; Genes; Genetic; Genetic Determinism; Genotype; Human; Hybrids; Hypertension; Inbred Strain; Individual; Inner mitochondrial membrane; Intervention; Investigation; Kidney; Lecithin; Lipids; Lod Score; Mediating; Mesenchymal; Mesenchyme; Metanephric Diverticulum; Mitochondria; Modeling; Morphology; Mouse Strains; Mus; Mutation; Nephrology; Nephrons; Organogenesis; Outcome; Partner in relationship; Perinatal; Phenotype; Physicians; Population; Pregnancy; Premature Birth; Principal Investigator; Process; Quantitative Trait Loci; Renal Tissue; Renal function; Reporting; Research; Research Training; Respiration; Risk; Scientist; Series; Signal Transduction; Structure; System; TSC1 gene; Testing; Therapeutic; Tissues; Trees; Variant; WNT Signaling Pathway; burden of illness; cohort; conditional mutant; design; diagnostic screening; epithelial to mesenchymal transition; experimental study; genomic locus; mouse model; mutant; mutant mouse model; nephrogenesis; nephron progenitor; novel diagnostics; novel therapeutic intervention; offspring; postnatal; premature; prenatal; progenitor; programs; self-renewal; stem cells; therapeutic target; trait; treatment strategy

PROJECT SUMMARY & ABSTRACT Mammalian kidney function is critically dependent on the number of nephrons generated during renal development. Nephrons are the filtration unit of the renal system and arise from a nephron progenitor cell (NPC) population at the periphery of the developing tissue. NPCs interact with the surrounding ureteric bud (UB) and stromal compartments, balancing self-renewal and differentiation into segmented nephron structures via a mesenchymal-to-epithelial transition. Consequently, nephron endowment is a quantitative outcome determined by several processes including UB branching and NPC dynamics. Two noteworthy aspects of mammalian renal development are: (1) a 10-fold variation in nephron number (NN) between human kidneys from different individuals, ranging from 200,000 to >2.5 million units per kidney and (2) the synchronous depletion of remaining progenitors at postnatal day 3 in mice (gestational week 34-37 in humans). These facts pose compelling research questions, as the genetic contributions to these aspects of renal organogenesis are not currently known. From a clinical standpoint, a low nephron endowment, which is particularly prevalent in premature birth cohorts, contributes to high blood pressure and chronic kidney disease (CKD). These conditions pose an immense disease burden worldwide, particularly as there is no known postnatal generation of new nephrons. While various genetic and perinatal factors are demonstrated to reduce NN, there remains a clear need to identify genetic contributions to the variation in and upper limits of nephron endowment. The principal investigator herein has identified that distinct mouse strains can be used to model and dissect the genetic basis of differences in nephron number, as several inbred strains and diversity outbred hybrids exhibit distinct, consistent NN phenotypes. Therefore, this proposal sets forth a strategy to identify and subsequently target genetic loci that modify NN outcomes, leveraging QTL mapping algorithms, sequencing data and known gene expression patterns in renal tissue. Secondarily, on a mechanistic basis, it is unclear whether NN variation arises from altered cessation timing, intrinsic changes in NPC activity, or a combination thereof; cellular energetics and mitochondrial function have been implicated. Thus, this proposal will also investigate a mitochondrial mutant mouse model, which exhibits NN elevated above baseline littermate controls, to identify mechanisms by which nephrogenesis can be enhanced. Collectively, by identifying targets and mechanisms that segregate with either high or low nephron number, this research will contribute to the ability to develop diagnostic screens and interventional treatment strategies for deficient nephrogenesis, respectively. Comprehensively, this research plan will aptly be executed in the fulfillment of a fellowship research training plan aimed at fostering the development of an independent physician-scientist in academic pediatric nephrology.

项目概要和摘要 哺乳动物的肾功能严重依赖于肾功能过程中产生的肾单位数量。 发展。肾单位是肾脏系统的过滤单位，由肾单位祖细胞 (NPC) 产生 发育组织外围的人口。 NPC 与周围的输尿管芽 (UB) 相互作用并 基质隔室，通过a平衡自我更新和分化为分段肾单位结构 间质到上皮的转变。因此，肾单位禀赋是一个定量结果 包括 UB 分支和 NPC 动力学在内的多个过程。哺乳动物肾脏的两个值得注意的方面 发展是：（1）来自不同国家的人类肾脏之间的肾单位数量（NN）有10倍的差异 个体，每个肾脏 200,000 到 >250 万单位不等，以及 (2) 剩余的同步消耗 小鼠出生后第 3 天（人类妊娠第 34-37 周）的祖细胞。这些事实提出了令人信服的研究 问题，因为目前尚不清楚遗传对肾器官发生这些方面的贡献。从 从临床角度来看，肾单位禀赋较低，这在早产儿群体中尤其普遍， 导致高血压和慢性肾病（CKD）。这些条件构成了巨大的 全世界的疾病负担，特别是因为没有已知的出生后新肾单位的产生。虽然各种 遗传和围产期因素已被证明可以减少 NN，但仍然需要确定遗传因素 对肾单位禀赋变化和上限的贡献。本文的主要研究者有 发现不同的小鼠品系可用于建模和剖析肾单位差异的遗传基础 数，因为一些近交系和多样性远交杂种表现出独特、一致的 NN 表型。 因此，该提案提出了一种策略来识别并随后靶向修饰 NN 的遗传位点 结果，利用 QTL 作图算法、测序数据和肾脏中已知的基因表达模式 组织。其次，从机制上讲，目前还不清楚神经网络变异是否是由停止的改变引起的 NPC 活动的时间、内在变化或其组合；细胞能量学和线粒体功能 都受到了牵连。因此，该提案还将研究线粒体突变小鼠模型，该模型 表现出 NN 高于同窝对照基线，以确定肾发生的机制 增强。总的来说，通过识别与高肾单位或低肾单位分离的目标和机制 数字，这项研究将有助于开发诊断屏幕和介入治疗的能力 分别针对肾发生缺陷的策略。 综合而言，该研究计划将在完成奖学金研究培训计划时得到适当执行 旨在培养学术儿科肾病学领域的独立医师科学家的发展。