Mechanism of Action of COUP-Transcription Factors

描述（由申请人提供）：慢性肾脏疾病是影响超过3000万美国人的主要健康问题，其发病率在过去十年中以惊人的16%的速度增长。肾脏是一个复杂的器官，需要不同的细胞类型和复杂的基因网络协调调节，以确保其正常发育和功能。因此肾脏疾病是多因素和复杂的。肾衰竭进展的根本原因以及肾脏疾病的治疗和预防仍然是一个挑战。我们发现COUP-TFII是一种调节细胞命运决定、胚胎发育和成人器官功能的转录因子，在肾脏发育、功能和疾病中发挥作用。几种主要的肾细胞类型表达COUP-TFII。在肾脏发育初期（E10.5）， COUP-TFII在肾后胚芽、泌尿生殖嵴和肾后间质（MM）中表达。输尿管芽生长后，COUP-TFII在输尿管芽周围的凝聚间质和肾小泡中表达。在肾形成阶段（E13.5）， COUP-TFII在远端小管和肾小球（足细胞和Bowman’s capsule）中高表达，但在近端小管中未检测到。早期有条件消融COUP-TFII时，MM不能正常形成，不形成肾脏。当COUP-TFII在后期被敲除时，很少有肾元可见，也没有可检测到的远端小管，这表明COUP-TFII对肾元的形成和模式至关重要。此外，失去一个COUP-TFII等位基因的成年小鼠表现为多囊肾、肾小球硬化（FSGS）和肾功能丧失，表型类似于人类肾脏疾病。初步结果提示，COUP-TFII可调节血管生成素1、WT1、PKD1、TGF及多种炎症基因的表达，提示COUP-TFII可能具有保护肾脏免受纤维化、炎症及糖尿病并发症的作用。为了进一步明确COUP-TFII突变体的缺陷，剖析COUP-TFII作用的潜在机制，我们在未来5年的具体目标是：1)阐明COUP-TFII在肾脏发育中的作用及其潜在机制；2)确定COUP-TFII在肾脏功能和疾病中的作用；3)确定COUP-TFII在糖尿病肾病中的作用。了解COUP-TFII在这些疾病中的确切作用将为肾脏疾病的治疗和干预提供及时的见解。

DESCRIPTION (provided by applicant): Chronic kidney diseases are major health problems that affect over 30 million Americans and the incidence is increasing at an alarming 16% in the last decade. The kidney is an intricate organ that requires coordinated regulation by distinct cell types and complex networks of genes to ensure its proper development and function. Kidney diseases are thus multifactorial and complex. The underlying causes to progression to kidney failure and the treatment and prevention of kidney diseases remain a challenge. We discovered that COUP-TFII, a transcription factor that regulates cell fate determination, embryonic development and adult organ function, plays a role in kidney development, function and disease. Several major cell types in the kidney express COUP-TFII. At the onset of kidney development (E10.5), COUP-TFII is expressed in the metanephric blastema, the urogenital ridge, and the metanephric mesenchyme (MM). Upon ureteric bud outgrowth, COUP-TFII is expressed in the condensed mesenchyme surrounding the ureteric buds and in the renal vesicle. At the nephrongenesis stage (E13.5), COUP-TFII becomes regionalized with high expression in the distal tubules and the glomeruli (podocytes and Bowman's capsule), but not detected in the proximal tubules. When COUP-TFII is conditionally ablated early, the MM cannot form properly and no kidney is formed. When COUP-TFII is knocked out at a later stage, very few nephrons are apparent and there is no detectable distal tubule, suggesting that COUP-TFII is critical for the formation and patterning of the nephron. Furthermore, adult mice with the loss of one COUP-TFII allele display polycystic kidneys, glomerulosclerosis (FSGS) and loss of kidney function, phenotypes resembling human kidney diseases. Preliminary results suggest that COUP-TFII regulates the expression of Angiopoietin 1, WT1, PKD1, TGF and many inflammatory genes, raising the possibility that COUP-TFII functions to protect the kidney from fibrosis, inflammation and from diabetic complications. To further define the defects of COUP-TFII mutants and dissect the underlying mechanism of COUP-TFII action, our specific aims in the next five years are: 1) Delineate the role of COUP-TFII in kidney development and its underlying mechanism; 2) Determine the role of COUP-TFII in kidney function and diseases; and 3) Determine the role of COUP-TFII in diabetic nephropathy. Understanding the precise role of COUP-TFII in these diseases will provide timely insights that could be used in therapeutic strategies for the treatment and intervention of kidney diseases. PUBLIC HEALTH RELEVANCE: Kidney diseases are major health hazards that affect over 30 million Americans. The various COUP-TFII deficient mouse models generated here will reveal how COUP-TFII affects kidney development and disease progression. Understanding COUP-TFII's mechanism of action will provide new avenues for the treatment of kidney diseases and diabetic complications.