Exploiting AMPK to Slow Polycystic Kidney Disease

描述（由申请人提供）：常染色体显性多囊肾病（ADPKD）是最常见的遗传性疾病，影响至少60万美国人。它的特点是巨大的囊性生长和肾脏扩大，最终进展为肾衰竭。目前没有FDA批准的ADPKD药物治疗。肾囊肿的形成是由于过多的顶端液体分泌到囊腔和肾上皮细胞的不适当增殖。这些过程被认为分别由CFTR氯离子通道和mTOR途径介导。这两个靶点都位于单磷酸腺苷激活蛋白激酶（AMPK）的下游，并被其拮抗。以前的治疗方法都是针对这两个过程中的一个或另一个。我们假设，如果AMPK被刺激，那么这将进一步抑制CFTR和mTOR，导致膀胱生成减少。本研究将寻求利用AMPK的活性来进一步抑制在肾囊肿疾病中观察到的异常分泌和增殖，目的如下：（1）表征AMPK刺激对其在肾上皮细胞中的下游靶标的影响，和（2.）评价在囊性肾病背景下二甲双胍诱导的AMPK抑制mTOR和CFTR的体外和体内作用。这些研究不仅将进一步了解AMPK在PKD发病机制中的作用，而且具有临床应用的潜力，因为AMPK的药理学激活剂二甲双胍已经被FDA批准用于治疗其他病症，相对便宜，毒性低。多囊肾是一种常见的遗传性疾病，其中患者出生时肾脏正常，发展为破坏正常肾脏的充满大量液体的囊肿。目前没有批准的药物治疗这种情况，只有透析。该研究项目旨在开发多囊肾疾病的药物治疗，并为这些患者提供另一种选择。

DESCRIPTION (provided by applicant): Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent genetic disease, affecting at least 600,000 Americans. It is characterized by massive cystic growth and enlargement of the kidneys, ultimately progressing to renal failure. There are currently no FDA-approved pharmaceutical therapies for ADPKD. Renal cyst formation is attributed to both excess apical fluid secretion into the cyst lumen and inappropriate proliferation of the renal epithelial cells. These processes are thought to be mediated by the CFTR chloride channel and the mTOR pathway, respectively. Both of these targets lie downstream of and are antagonized by Adenosine Monophosphate-activated Protein Kinase (AMPK). Previous therapies have been targeted to address one or the other of these two processes. We hypothesize that if AMPK is stimulated, then this will further the inhibition of both CFTR and mTOR, leading to decreased cystogenesis. This study will seek to exploit the activity of AMPK to further inhibit the abnormal secretion and proliferation observed in renal cystic disease with the following Aims: (1.) Characterize the effects of AMPK stimulation on its downstream targets in renal epithelia, and (2.) Evaluate the in vitro and in vivo effects of metformin-induced AMPK inhibition of mTOR and CFTR in the context of cystic kidney disease. These studies will not only further the understanding the role of AMPK in the pathogenesis of PKD, but also have the potential for clinical application as metformin, a pharmacological activator of AMPK is already FDA approved for the treatment of other conditions, is relatively inexpensive, and has low toxicity. Polycystic kidney disease is a common inherited disease in which patients born with normal kidneys develop large fluid filled cysts that destroy the normal kidney. There are currently no approved medications for this condition, just dialysis. This research project is aimed at developing a drug therapy for polycystic kidney disease, and giving these patients another option.