A role for mRNA transport and local translation in podocytes

描述（由申请人提供）：足细胞是肾脏过滤器（肾小球）中的关键细胞类型。我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，从而预防终末期肾病（ERSD）。目前，儿童和成人的慢性肾脏疾病导致不可逆的肾损伤和终身透析或肾移植。这对患者及其家庭来说是一个沉重的负担，每年花费医疗保健系统数十亿美元。在过去的几年中，足细胞足突（长的富含肌动蛋白的细胞延伸）的不可逆损伤导致蛋白质大量丢失，最终导致肾小球硬化和ESRD已经变得很明显。然而，存在足细胞能够从短暂损伤中恢复的临床病症（例如微小变化疾病），这表明它们具有重建足突结构的内在机制。我们已经开发的证据表明，足细胞使用细胞质核糖核蛋白颗粒（RNP）或RNA颗粒存储在其足突的局部翻译，在类似的方式作为另一种极化细胞类型，神经元的沉默mRNA。这项资助将继续我们对RNA颗粒作为一种适应机制的作用的研究，这种适应机制参与维持足突结构，从而预防终末期肾病。两个主要焦点将是在调节足细胞中的mRNA定位的RNA结合蛋白Staufen 2的作用和Staufen 2和Staufen 2相关的miRNA在足细胞足突的细胞骨架组装中的作用，无论是在生理条件下还是在对损伤的反应中。对这一生理途径的更深入了解可能最终导致设计新的治疗药物，以防止足细胞足突和ESRD的不可逆损伤。

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.