A role for mRNA transport and local translation in podocytes

描述(申请人提供)：足细胞是肾脏滤过装置(肾小球)中的一种重要细胞类型。我的实验室研究的长期目标是开发新的治疗方法，提高足细胞的再生能力，从而预防终末期肾脏疾病(ERSD)。目前，儿童和成人的慢性肾脏疾病会导致不可逆转的肾脏损害和终生透析或肾移植。这对患者及其家人来说是一个沉重的负担，并每年花费医疗保健系统数十亿美元。在过去的几年里，足细胞足突(长的富含肌动蛋白的细胞延伸)的不可逆转的损害已经变得明显，导致蛋白质的大量损失，最终导致肾小球硬化和终末期肾病。然而，临床上存在足细胞能够从一过性损伤中恢复的临床情况(如微小病变)，这表明它们具有重建足突结构的内在机制。我们已经找到证据表明，足细胞使用细胞质核糖核蛋白颗粒(RNP)或RNA颗粒在其足突中储存翻译沉默的mRNAs进行局部翻译，方式与另一种极化细胞类型神经元相似。这笔赠款将继续我们对RNA颗粒作为一种适应性机制的作用的研究，该机制涉及维持足部过程架构，从而预防ESRD。两个主要的焦点将是RNA结合蛋白Staufen 2在调节足细胞mRNA定位中的作用，以及Staufen 2和Staufen 2相关的miRNAs在生理条件下和损伤反应中足细胞足突的细胞骨架组装中的作用。对这一生理途径的进一步了解可能最终导致新的治疗药物的设计，这些药物将防止足细胞足突和ESRD受到不可逆转的损害。

DESCRIPTION (provided by applicant): Podocytes are a crucial cell type in the filtering apparatus (glomerulus) of the kidney. The long-term goal of my laboratory's research is to develop new treatments that improve the regenerative capability of podocytes, and thus prevent end-stage renal disease (ERSD). At present, chronic renal disease in children and adults leads to irreversible kidney damage and lifelong dialysis or kidney transplantation. This represents a significant burden for patients and their families, and costs the health care system billions of dollars annually. Over the past several years, it has become evident that irreversible damage to podocyte foot processes (long actin-rich cell extensions) leads to massive loss of protein and ultimately to glomerulosclerosis and ESRD. There exist however clinical conditions (e.g. minimal change disease), in which podocytes are able to recover from transient damage, suggesting that they possess intrinsic mechanisms to re-establish foot process architecture. We have developed evidence that podocytes use cytoplasmic ribonucleoprotein particles (RNPs) or RNA granules to store translationally silent mRNAs within their foot processes for local translation, in a similar manner as another polarized cell type, the neuron. This grant will continue our studies on the role of RNA granules as an adaptive mechanism involved in maintaining foot process architecture and thus preventing ESRD. Two major foci will be on the role of the RNA binding protein Staufen 2 in regulating mRNA localization in podocytes and the role of Staufen 2 and Staufen 2-associated miRNAs in the cytoskeletal assembly of podocyte foot processes both under physiological conditions and in response to injury. A greater understanding of this physiologic pathway may eventually result in the design of new therapeutic agents that will prevent irreversible damage to podocyte foot processes and ESRD.