Cystic Fibrosis (CF) is a fatal, inherited disease caused by loss-of-function mutations in the Cystic Fibrosis transmembrane conductance regulator (CFTR), a chloride channel expressed in epithelial cells of various organs. CF is a multi-organ disease that affects the respiratory tract, digestive tract, and exocrine organs. Deletion of phenylalanine at the F508del CFTR position in CFTR is the most common mutation contributing to CF. F508del-CFTR is classified as class II due to its instability at the endoplasmic reticulum (ER). In 2018, Vertex's Trikafta was approved for treating CF, which treats the underlying hereditary cause. However, there is a need for a new therapeutic approach for the treatment of other mutations for which Trikafta appears to be ineffective. The research focuses on identifying the E2 enzymes responsible for CFTR proteostasis with the idea of targeting E2 enzymes instead of E1 enzymes to correct the F508del-CFTR proteostasis defect. The effect of the NSC inhibiton on CFBE cells, which are immortalized cells from an F508del-CFTR homozygous patient stably overexpressing F508del-CFTR. The results show that NSC treatment restores the F508del-CFTR channel activity to WT levels, demonstrating that E2 enzymes play an important role in F508del-CFTR proteostasis. The research proposes a new therapeutic strategy to correct the F508del-CFTR proteostasis defect.
Cystic Fibrosis (CF) is a fatal, inherited disease caused by loss-of-function mutations in the Cystic Fibrosis transmembrane conductance regulator (CFTR), a chloride channel expressed in epithelial cells of various organs. CF is a multi-organ disease that affects the respiratory tract, digestive tract, and exocrine organs. Deletion of phenylalanine at the F508del CFTR position in CFTR is the most common mutation contributing to CF. F508del-CFTR is classified as class II due to its instability at the endoplasmic reticulum (ER). In 2018, Vertex's Trikafta was approved for treating CF, which treats the underlying hereditary cause. However, there is a need for a new therapeutic approach for the treatment of other mutations for which Trikafta appears to be ineffective. The research focuses on identifying the E2 enzymes responsible for CFTR proteostasis with the idea of targeting E2 enzymes instead of E1 enzymes to correct the F508del-CFTR proteostasis defect. The effect of the NSC inhibitor on CFBE cells, which are immortalized cells from an F508del-CFTR homozygous patient stably overexpressing F508del-CFTR. The results show that NSC treatment restores the F508del-CFTR channel activity to WT levels, demonstrating that E2 enzymes play an important role in F508del-CFTR proteostasis. The research proposes a new therapeutic strategy to correct the F508del-CFTR proteostasis defect.
TARGETING UBIQUITINATION MACHINERY FOR THE RESCUE OF THE F508del-CFTR
KHASKHELI, HAMEER KHAN
2022/2023
Abstract
Cystic Fibrosis (CF) is a fatal, inherited disease caused by loss-of-function mutations in the Cystic Fibrosis transmembrane conductance regulator (CFTR), a chloride channel expressed in epithelial cells of various organs. CF is a multi-organ disease that affects the respiratory tract, digestive tract, and exocrine organs. Deletion of phenylalanine at the F508del CFTR position in CFTR is the most common mutation contributing to CF. F508del-CFTR is classified as class II due to its instability at the endoplasmic reticulum (ER). In 2018, Vertex's Trikafta was approved for treating CF, which treats the underlying hereditary cause. However, there is a need for a new therapeutic approach for the treatment of other mutations for which Trikafta appears to be ineffective. The research focuses on identifying the E2 enzymes responsible for CFTR proteostasis with the idea of targeting E2 enzymes instead of E1 enzymes to correct the F508del-CFTR proteostasis defect. The effect of the NSC inhibiton on CFBE cells, which are immortalized cells from an F508del-CFTR homozygous patient stably overexpressing F508del-CFTR. The results show that NSC treatment restores the F508del-CFTR channel activity to WT levels, demonstrating that E2 enzymes play an important role in F508del-CFTR proteostasis. The research proposes a new therapeutic strategy to correct the F508del-CFTR proteostasis defect.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/49902