Genetic Regulation of Nephron Progenitor Cells in the Mammalian Kidney

哺乳动物肾脏中肾单位祖细胞的遗传调控

• 批准号: 9258421
• 负责人: Akio Kobayashi
• 金额: $ 37.85万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258421
• 关键词: Cell Differentiation process; Cell Maintenance; Cells; Choristoma; Chronic Kidney Failure; Coloboma; Complement; Congenital Disorders; Data; Defect; Development; Dialysis procedure; Disease model; Dysplasia; End stage renal failure; Endowment; Essential Genes; Family; Future; Gene Expression Profile; Genes; Genetic; Goals; Hypertension; In Vitro; Integrins; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Lead; Maintenance; Malnutrition; Maps; Mediator of activation protein; Mesenchyme; Microarray Analysis; Molecular; Mus; Mutation; Nephrons; Optic Nerve; Pathologic; Patients; Phenotype; Population; Pregnancy; Premature Birth; Protocols documentation; Regenerative Medicine; Regulation; Renal Replacement Therapy; Repression; Resources; Series; Specific qualifier value; Stem cells; Syndrome; Testing; Therapeutic; Time; Tissues; To specify; Toxicity Tests; developmental disease; experimental study; gain of function; health economics; in vivo; interstitial; interstitial cell; kidney interstitial tissue; mutant; nephrogenesis; novel therapeutic intervention; premature; progenitor; public health relevance; regenerative; self-renewal; transdifferentiation

DESCRIPTION (provided by applicant): Reduced endowment of the nephrons, the basic functional units of the kidney, is associated with future development of hypertension and even chronic kidney disease (CKD), ultimately leading to end stage renal disease (ESRD), a significant, growing economic health burden in the US. The PI has previously identified that the cap mesenchyme is a multipotent self-renewing nephron progenitor population during mammalian kidney development. It is critical to understand how cap mesenchyme cells are regulated during kidney development in order to develop therapeutic approaches to increase nephron endowment in situations like prematurity or malnutrition. Renal-coloboma syndrome (RCS) is a congenital developmental disorder characterized by renal hypodysplasia with reduced nephron numbers caused by PAX2 mutations. Although Pax2 has been widely recognized as an important factor for kidney development over the past two decades, Pax2 function in the developing kidney has not been investigated in vivo. Our central hypothesis supported by extensive preliminary data is that Pax2 function maintains the nephron lineage by repressing trans-differentiation into interstitial cell fates in the cap mesenchyme. In the Aim 1, we will determine cellular mechanisms for the trans-differentiation by molecular characterization of intermediate and terminally trans-differentiated cell states. We will also test whether Pax2 is sufficient to specify cap mesenchyme. In the Aim 2, we will distinguish Pax2 functions in the cap mesenchyme and differentiating nephron cells by comparing stage-specific Pax2 mutants before and after the onset of nephron differentiation. In the Aim 3, we will test our hypothesis that integrin �8 activity for maintenance of the nephron lineage, acting downstream of Pax2 in cap mesenchyme cells. Results from our proposed studies will initiate to uncover the genetic networks in nephron progenitor cells regulating the lineage boundary to maintain the nephron compartment during formation of the functional kidney with the full complement of nephrons.

描述（由申请方提供）：肾单位（肾脏的基本功能单位）的禀赋降低与未来高血压甚至慢性肾脏疾病（CKD）的发展相关，最终导致终末期肾脏疾病（ESRD），这是美国一种显著且不断增长的经济健康负担。PI先前已经确定帽间充质是哺乳动物肾脏发育过程中的多能自我更新肾单位祖细胞群。关键是要了解帽间充质细胞是如何在肾脏发育过程中进行调节，以开发治疗方法，以增加肾单位禀赋的情况下，如早产或营养不良。肾缺损综合征（RCS）是一种先天性发育障碍，其特征是PAX2突变引起的肾发育不全伴肾单位数量减少。尽管Pax2在过去二十年中被广泛认为是肾脏发育的重要因素，但尚未在体内研究Pax2在发育中的肾脏中的功能。我们的中心假设支持广泛的初步数据是，Pax2功能维持肾单位谱系抑制转分化成间质细胞的帽间充质细胞的命运。在目标1中，我们将通过中间和终末转分化细胞状态的分子表征来确定转分化的细胞机制。我们还将测试Pax2是否足以指定帽间充质。在目标2中，我们将通过比较肾单位分化开始之前和之后的阶段特异性Pax2突变体来区分Pax2在帽间充质和分化的肾单位细胞中的功能。在目标3中，我们将测试我们的假设，即整合素β 8活性维持肾单位谱系，作用于帽间充质细胞中Pax2的下游。从我们提出的研究结果将开始揭示肾单位祖细胞的遗传网络调节谱系边界，以维持肾单位隔室在形成功能肾与完整的肾单位。