[R01] Identifying the Therapeutic Potential and Molecular Mechanism of lnc-Hoxb3os in ADPKD

Ente: National Institute of Diabetes and Digestive and Kidney Diseases

Scadenza: 2030-05-31

Importo max: 785.689 EUR

Paese: US

Descrizione

PROJECT SUMMARY Polycystic kidney disease (PKD) is characterized by the formation of cysts, which originate from the epithelial tubules of the nephron. The most common form of PKD, autosomal dominant polycystic kidney disease (ADPKD), is primarily caused by mutations in two genes, PKD1 and PKD2. More than 600,000 people in the United States are affected by this disease. About half of those diagnosed with ADPKD will progress to end-stage renal failure, necessitating dialysis or kidney transplantation. The pathophysiology of ADPKD is incompletely understood, and only one FDA-approved treatment (tolvaptan) exists. Accordingly, there is an urgent need to elucidate the molecular mechanisms of disease onset and progression toward the goal of identifying new drug targets and developing the next generation of effective therapeutics. Long noncoding RNAs (lncRNAs) – defined by a length >200 nucleotides and absence of a long open reading frame-are a class of non-protein-coding RNAs implicated in a range of diseases. The nature and extent of involvement of lncRNAs in ADPKD are not well known. Our long-term goal is to identify therapeutically targetable lncRNAs that prevent or mitigate cyst formation and/or progression in ADPKD. We recently identified Hoxb3os as the first lncRNA that is directly involved in mouse PKD. Hoxb3os was reduced in cystic kidneys from multiple mouse models of PKD, its ablation exacerbated cystogenesis in rapid- and slow-progressing PKD mouse models. The human ortholog, HOXB-AS1, is similarly decreased in human ADPKD kidneys and in cystic kidney organoids. At the molecular level, we discovered that Hoxb3os RNA associates with 16 proteins in kidney cells, including PKM2 and ATP synthase (ATP5F1A/B), two nodes central to ADPKD metabolism. Hoxb3os-mutant cells displayed increased glycolysis and enhanced mitochondrial superoxide production. Our central hypothesis is that Hoxb3os/HOXB-AS1 suppresses cystogenesis by inhibiting glycolysis and reducing mitochondrial superoxide through direct interactions with PKM2 and ATP5F1A/B, respectively. To test this hypothesis, we will 1) determine whether re- expressing Hoxb3os in mouse PKD and HOXB-AS1 in human ADPKD models reduces cyst burden and improves functional readouts, and 2) identify the mechanisms by which Hoxb3os/HOXB-AS1 regulates glycolysis and mitochondrial superoxide. Because glycolytic reprogramming and mitochondrial ROS are key drivers of ADPKD, these studies will define a lncRNA-guided metabolic control axis and lay the groundwork for RNA-based therapeutics and companion diagnostics for cystic kidney disease. Istituzione: STATE UNIVERSITY NEW YORK STONY BROOK PI: Karam Aboudehen Progetto: 1R01DK143971-01A1

Settori: National Institute of Diabetes and Digestive and Kidney Diseases

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