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

常染色体显性多囊肾病的驱动机制：RNA 结合蛋白 ANKHD1 的新作用。

• 批准号: MR/T04201X/2
• 负责人: Maria Fragiadaki
• 金额: $ 72.13万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT04201X%2F2
• 关键词: Mechanisms; driving; Autosomal; Dominant; Polycystic

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.

Please try later.

项目成果

Evaluating the Molecular Properties and Function of ANKHD1, and Its Role in Cancer.

• DOI: 10.3390/ijms241612834
• 发表时间: 2023-08-16
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Mullenger, Jordan L.;Zeidler, Martin P.;Fragiadaki, Maria
• 通讯作者: Fragiadaki, Maria

Investigation of Perception of Quality of Life and Psychological Burden of Patients Undergoing Hemodialysis-Quality of Life of Hemodialysis Patients.

• DOI: 10.3390/nursrep13030112
• 发表时间: 2023-09-19
• 期刊: Nursing reports (Pavia, Italy)
• 作者: Rikos N;Kassotaki A;Frantzeskaki C;Fragiadaki M;Mpalaskas A;Vasilopoulos G;Linardakis M
• 通讯作者: Linardakis M