LIPID-BASED APPROACHES TO OPTIMIZE THE EFFECTIVENESS OF INNOVATIVE DRUG MODULATORS IN CYSTIC FIBROSIS
type: CreativeWork
description: Cystic Fibrosis (CF), a life-threatening hereditary disease prevalent among Caucasians, results from mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. This gene encodes a chloride-conducting transmembrane channel crucial for ion transport across epithelial cells. CFTR mutations lead to impaired expression and function of the channel, causing disrupted chloride ion transport in secretory epithelia. Severe manifestations affect many organs, primarily the respiratory system, with impaired mucociliary clearance and airway surface liquid dehydration, leading to recurrent infections and high morbidity. The most common mutation, the deletion of phenylalanine at position 508 (F508del), induces misfolding and retention of CFTR in the endoplasmic reticulum, causing premature degradation. In airway epithelial cells, CFTR associates with proteins in a macromolecular complex, and its channel activity and surface expression are regulated by local signaling and recycling through endosomal compartments. The CFTR interactome also includes lipids, such as cholesterol and sphingolipids, that play a significant role in stabilizing CFTR within the cell membrane, particularly in specialized regions known as lipid rafts. In fact, the ganglioside GM1 is an important bioactive sphingolipid that has been reported to play a crucial role in the control of several plasma membrane (PM) proteins and its correlation with CFTR prompts speculations about its possible role in the CFTR interactome. Despite therapeutic improvements that extended CF patients' life expectancy, a cure remains elusive. Promising strategies involve CFTR-modulators, such as correctors, enhancing CFTR biosynthesis and trafficking, and potentiators, ameliorating mutated channel function. Treatment of patients having F508del mutation requires a combination of correctors and potentiators. Indeed, recent advancements in therapy encompass the triple combination Kaftrio (comprising two correctors, VX…
abstract: Cystic Fibrosis (CF), a life-threatening hereditary disease prevalent among Caucasians, results from mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. This gene encodes a chloride-conducting transmembrane channel crucial for ion transport across epithelial cells. CFTR mutations lead to impaired expression and function of the channel, causing disrupted chloride ion transport in secretory epithelia. Severe manifestations affect many organs, primarily the respiratory system, with impaired mucociliary clearance and airway surface liquid dehydration, leading to recurrent infections and high morbidity. The most common mutation, the deletion of phenylalanine at position 508 (F508del), induces misfolding and retention of CFTR in the endoplasmic reticulum, causing premature degradation. In airway epithelial cells, CFTR associates with proteins in a macromolecular complex, and its channel activity and surface expression are regulated by local signaling and recycling through endosomal compartments. The CFTR interactome also includes lipids, such as cholesterol and sphingolipids, that play a significant role in stabilizing CFTR within the cell membrane, particularly in specialized regions known as lipid rafts. In fact, the ganglioside GM1 is an important bioactive sphingolipid that has been reported to play a crucial role in the control of several plasma membrane (PM) proteins and its correlation with CFTR prompts speculations about its possible role in the CFTR interactome. Despite therapeutic improvements that extended CF patients' life expectancy, a cure remains elusive. Promising strategies involve CFTR-modulators, such as correctors, enhancing CFTR biosynthesis and trafficking, and potentiators, ameliorating mutated channel function. Treatment of patients having F508del mutation requires a combination of correctors and potentiators. Indeed, recent advancements in therapy encompass the triple combination Kaftrio (comprising two correctors, VX…
author: DOBI, DORINA
language: eng
keywords: Settore BIO/10 - Biochimica
date published: 2024-06-10
date modified: 2026-07-27T20:19:00Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/1045776

PropertyValue
property ID: DOI
value: 10.13130/dobi-dorina_phd2024-06-10