Mechanisms driving Autosomal Dominant Polycystic Kidney Disease: The novel role of the RNA-binding protein ANKHD1.

本FLF提案旨在提高对常染色体显性多囊肾病（ADPKD）病因的理解，以发现阻止疾病进展的新药。ADPKD是最常见的遗传性肾脏疾病，影响着全球超过1200万人。其中，50%的人在50岁时将失去肾功能，需要肾脏移植或终身透析才能生存。目前可供移植的肾脏来源有限。更严重的是，由于严重的血管缺陷，很大比例的ADPKD患者会发生颅内动脉瘤。尽管托伐普坦是首个被批准用于ADPKD的药物，提供了强有力的证据，证明该疾病可以被改造，但它只有适度的治疗效果。此外，Tolvaptan有明显的副作用。因此，对新靶点的治疗需求尚未得到满足。因此，对新疗法的迫切需求以及该领域令人兴奋的进展意味着我对多囊肾病创新研究的建议是非常及时的。为了能够提供新的治疗方法，有必要了解肾脏中多个囊肿生长的过程。ADPKD中控制囊肿持续生长和过度细胞外基质（ECM）积累的机制尚不清楚。我的团队最近有了一个发现，有可能解开ADPKD发病机制。我发现了一种名为Ankhd1的基因，它通过控制一种新的RNA代谢机制来控制多囊肾的细胞增殖和纤维化。值得注意的是，在ADPKD的细胞和小鼠模型中，ankhd1缺乏可改善肾功能，减少囊性生长并限制纤维化。使用尖端的新方法，我发现ANKHD1通过直接与靶mrna相互作用来促进ADPKD。有趣的是，ANKHD1 RNA结合域的突变或缺失使该蛋白失活，这强烈表明ANKHD1通过mrna促进ADPKD。在这个提案中，我将发现ANKHD1调节的机制，导致细胞凋亡改变，增殖和纤维化增加，从而使细胞“活化”。为了研究新发现的基因对疾病的贡献，有必要使用人类细胞和小鼠，这将密切模拟人类疾病。此外，我将描述改变的RNA代谢如何促进adpkd介导的血管功能障碍。这个雄心勃勃的多学科项目将为新的核酸基化合物的临床试验铺平道路，以阻止ADPKD的进展。为了最大限度地发挥项目影响和领导潜力，我将奖学金发展计划与研究目标相结合，并朝着7年计划的转化目标迈进。发展计划包括实地考察世界领先的实验室，学习新的前沿方法，我计划把它带回谢菲尔德（eRIC， RBNS，计算管道）；官方培训（领导力，临床试验，pi的生物信息学）和通过在谢菲尔德举办英国基质生物学学会会议和ADPKD患者信息日来传播工作和创造新的机会。

This FLF proposal seeks to improve understanding of the cause of Autosomal Dominant Polycystic Kidney Disease (ADPKD), in order to discover new medicines to halt disease progression. ADPKD is the most common genetic renal disorder, affecting over 12 million people worldwide. Of those, 50% will lose kidney function by the age of 50, requiring either kidney transplantation or lifelong dialysis to survive. Currently we have a limited source of kidneys for transplantation. To add to this problem, a high proportion of patients with ADPKD develop intracranial aneurysms due to profound vascular defects. Although Tolvaptan is the first drug approved for ADPKD, providing strong evidence that the disease can be modified, it only has a modest therapeutic effect. Moreover, Tolvaptan comes with significant obligate side effects. Hence, there is a major unmet therapeutic need for new targets. Therefore, the urgent need for new therapies together with the exciting advancements in the field, mean that my proposal for innovative research in polycystic kidney disease is highly timely. To be in a position to offer new therapies, it is necessary to understand the processes by which growth of multiple cysts take place in the kidney. The mechanisms that control relentless growth of cysts and excessive extracellular matrix (ECM) accumulation in ADPKD are unknown. My group has recently made a discovery that has the potential to unlock the mechanisms of ADPKD pathogenesis. I discovered a gene, called Ankhd1, which controls cell proliferation and fibrosis in the polycystic kidney by controlling a novel RNA metabolism mechanism. Remarkably, Ankhd1-deficiency improves renal function, reduces cystic growth and limits fibrosis in cellular and mouse models of ADPKD. Using cutting-edge novel methods, I discovered that ANKHD1 promotes ADPKD by directly interacting with target mRNAs. Intriguingly, mutations or deletions in the RNA binding domain of ANKHD1 render the protein inactive, strongly suggesting that ANKHD1 promotes ADPKD via mRNAs. In this proposal, I will discover the mechanisms regulated by ANKHD1 that lead to altered apoptosis, increased proliferation and fibrosis, thus making cells 'activated'. To study the contribution of the newly identified genes to disease, it is necessary to use human cells and mice, which will model the human disease closely. Moreover, I will describe how altered RNA metabolism contributes to ADPKD-mediated vascular dysfunction. This ambitious multi-disciplinary programme will pave the way for a clinical trial of new nucleic-acid based compounds to halt ADPKD progression. To maximise project impact and leadership potential, I have integrated a Fellowship Development Plan with the research aims and builds towards the translational goal of the 7-year plan. The Development plan includes field visits to wold leading labs to learn new cutting edge methods, which I plan to bring back to Sheffield (eRIC, RBNS, computational pipelines); official training (leadership, clinical trials, bioinformatics for PIs) and dissemination of work and generation of new opportunities by hosting a British Society of Matrix Biology meeting in Sheffield and ADPKD patient information days.