NIH grant: Primary Cilia as Metabolic Regulators in Cholangiocyte Health and Disease (1R01CA314164-01A1)

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NIH grant 1R01CA314164-01A1: Primary Cilia as Metabolic Regulators in Cholangiocyte Health and Disease
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Sergio A Gradilone. Award: $626943.
Start: 2026-07-03T00:00:00.
Primary cilia are multisensory organelles that function as cellular antennae. Ciliary defects in cholangiocytes and/or the loss of primary cilia have been linked to biliary tract diseases like polycystic liver disease (PLD) and cholangiocarcinoma (CCA). A deeper understanding of cilia-regulated signaling pathways and the mechanisms underlying ciliary loss in diseased cholangiocytes is essential for developing novel ciliotherapy-based treatments aimed at restoring ciliary function. The long-term goals of this research are to understand the pathogenesis of the cholangiociliopathies and to develop innovative therapeutic strategies for their treatment. The overall objective for this proposal is to explore the novel hypothesis that the cholangiocyte primary cilium regulates the cellular metabolic phenotype. The CENTRAL HYPOTHESES are that: (a) sensory functions of primary cilia negatively regulate glucose consumption, and (b) in CCA, defects on primary cilia induce a metabolic switch to aerobic glycolysis. Two integrated but independent aims will test these hypotheses.
Aim 1, This aim will determine how primary cilia loss drives metabolic reprogramming in cholangiocytes and contributes to cholangiocarcinoma progression. In this aim, we will investigate the consequences of ciliary dysfunction on cellular metabolism (glycolytic switch) and tumor behavior, using normal (ciliated vs. deciliated) and CCA cell lines, xenograft/orthotopic models, and human CCA specimens. We will also evaluate whether reversing the Warburg effect (via HK2 inhibition) slows CCA cell proliferation and tumor growth. We will characterize metabolic profiles of ciliary defective cells compared to normal ciliated cells by Seahorse Real-Time Cell Metabolic analyzer, molecular cell biology, immunohistochemistry, RNAseq, and metabolomics approaches. Aim 2, This aim will elucidate the cilia-dependent signaling mechanism (P2Y¨PKA¨LKB1¨HIF1ƒ¿ pathway) that regulates cholangiocyte metabolism, and test therapeutic strategies to restore this pathway in cholangiocarcinoma. This aim addresses the mechanism: we will dissect how ciliary sensory functions normally suppress HIF1ƒ¿ and glycolysis via LKB1/AMPK. We will use targeted interventions (e.g., activate LKB1 with a small molecule or inhibit HIF1ƒ¿) in cilia-defective CCA models to see if we can normalize metabolism and impede tumor growth. The aim will also incorporate verifying this pathway in patient samples (e.g., correlation of cilia status with LKB1 activation and HIF1ƒ¿ targets in CCA tissues). Impact: These experiments, conducted by an experienced and multidisciplinary team, will uncover novel and generalizable information on the fundamental mechanisms of ciliary-dependent regulation of the metabolic switch that influence the survival of cholangiocytes. Successful completion of these aims will uncover a novel metabolic vulnerability in CCA (the ciliary-Warburg axis) and provide preclinical evidence for ciliotherapy-based metabolic interventions as a new treatment strategy for cholangiocarcinoma. Animal studies are required to determine how primary cilia regulate cholangiocarcinoma metabolism and growth in vivo and to evaluate the therapeutic efficacy of targeting the ciliary-Warburg axis in physiologically relevant disease models.

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