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: 8506855
• 负责人: Akio Kobayashi
• 金额: $ 11.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2013-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506855
• 关键词: Cell Maintenance; Cells; Choristoma; Chronic Kidney Failure; Coloboma; Complement; 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; Patients; Phenotype; Population; Pregnancy; Premature Birth; Protocols documentation; Regenerative Medicine; Regulation; Renal Replacement Therapy; Repression; Resources; Series; Specific qualifier value; Staging; Stem cells; Syndrome; Testing; Therapeutic; Time; Tissues; To specify; Toxicity Tests; developmental disease; gain of function; health economics; in vivo; interstitial; interstitial cell; mutant; nephrogenesis; novel therapeutic intervention; premature; progenitor; public health relevance; regenerative; research study; self-renewal

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(由申请人提供)：肾脏的基本功能单位肾单位的捐赠减少，与高血压甚至慢性肾脏疾病(CKD)的未来发展相关，最终导致终末期肾脏疾病(ESRD)，这在美国是一个重大的、日益增长的经济健康负担。PI此前已证实，在哺乳动物肾脏发育过程中，帽间充质是一种多能自我更新的肾单位祖细胞。了解在肾脏发育过程中帽间充质细胞是如何调节的是至关重要的，以便开发治疗方法，在早产或营养不良的情况下增加肾单位的捐赠。肾错构瘤综合征(RCS)是一种以PAX2基因突变引起的肾发育不良、肾单位数目减少为特征的先天性发育障碍。虽然Pax2在过去二十年中被广泛认为是肾脏发育的重要因素，但Pax2在肾脏发育中的作用还没有在体内进行研究。我们的中心假设得到了大量初步数据的支持，即Pax2功能是通过抑制帽间充质中向间质细胞命运的转分化来维持肾单位的血统。在目标1中，我们将通过对中间和末端跨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Pax2在肾单位分化开始前后的阶段特异性突变来区分Pax2在帽间充质细胞和分化中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，整合素？8活性维持肾单位谱系，作用于帽间充质细胞中Pax2的下游。我们的研究结果将开始揭示肾单位祖细胞中调节谱系边界的遗传网络，以在具有完整肾单位的功能性肾脏形成过程中维持肾单位间隔。