{"id":{"repo_id":"wlv","oai_identifier":"oai:wlv.openrepository.com:2436/626006"},"canonical_url":"https://search.dev.ndltd.org/etd/wlv/oai:wlv.openrepository.com:2436/626006","repository":{"repo_id":"wlv","name":"University of Wolverhampton","base_url":"https://wlv.openrepository.com/server/oai/request"},"display":{"title":"Investigating WNT signalling in the lung","abstract":"Autosomal recessive polycystic kidney disease (ARPKD) is a rare hereditary condition that has been reported to affect approximately one in every 20,000 newborns worldwide. It is caused by a mutation in PKHD1, the gene encoding the protein Fibrocystin (FPC). The primary pathophysiology of ARPKD has been characterized by cystic kidney disease, liver fibrosis, and lung failure. The most severe cases of ARPKD have been observed in neonatal life, with a mortality rate of 30–40%, where the cause of death has been attributed to respiratory distress resulting from lung hypoplasia. If this stage is survived, the chances of long-term survival have been noted to increase to 80%. The specific etiology of this hypoplasia has remained unknown; however, it has been linked to kidney enlargement and oligohydramnios. As a branch of non-canonical WNT signalling, the planar cell polarity (PCP) pathway has emerged as a key ciliary signalling mechanism. Recent studies have highlighted the involvement of core PCP proteins in both ARPKD pathology and lung development and homeostasis. The aim of the study was to determine whether there was a link between non-canonical Wnt signalling and the PKHD1 mutation that was responsible for lung hypoplasia seen in ARPKD patients. Both lung tissue samples from 9-month-old Pkhd1T36M/T36M mice and A549 cells were used in this study. Key proteins from both canonical and non-canonical Wnt pathways were quantified by Western blotting to determine the primary intercellular Wnt signalling pathway associated with lung hypoplasia in ARPKD mutant mouse lungs. Following this, WNT4 and ATMIN single and double knockdowns, as well as WNT11 and PKD2 single and double knockdowns, were performed in A549 cells to assess the interrelationship between these genes and to determine their functional effects in lung epithelial cells. Several cellular functions, including apoptosis, proliferation, adhesion, migration, cell morphology, and actin cytoskeleton expression and localization, were examined. Studies on mouse lungs indicated that the PCP pathway was the primary pathway affected in Pkhd1-mutated mouse lungs, with observed changes in the protein expression of Vangl2 and Scribble. Meanwhile, studies on human lung cell lines suggested that WNT4, ATMIN, WNT11, and PKD2 could be potential regulators of lung development, particularly in branching morphogenesis, alveolar development, and angiogenesis. These findings suggested a contribution to the development of pulmonary hypoplasia in ARPKD patients, in contrast to the initial theory that pulmonary hypoplasia was a secondary effect of cystic and enlarged kidneys. Further investigations will be required to determine the direct involvement of Pkhd1 in lung development. If confirmed, these findings could aid in the development of effective diagnostic tools and therapeutic targets for pulmonary hypoplasia in ARPKD patients.","abstract_html":"Autosomal recessive polycystic kidney disease (ARPKD) is a rare hereditary condition that has been reported to affect approximately one in every 20,000 newborns worldwide. It is caused by a mutation in PKHD1, the gene encoding the protein Fibrocystin (FPC). The primary pathophysiology of ARPKD has been characterized by cystic kidney disease, liver fibrosis, and lung failure. The most severe cases of ARPKD have been observed in neonatal life, with a mortality rate of 30–40%, where the cause of death has been attributed to respiratory distress resulting from lung hypoplasia. If this stage is survived, the chances of long-term survival have been noted to increase to 80%. The specific etiology of this hypoplasia has remained unknown; however, it has been linked to kidney enlargement and oligohydramnios. As a branch of non-canonical WNT signalling, the planar cell polarity (PCP) pathway has emerged as a key ciliary signalling mechanism. Recent studies have highlighted the involvement of core PCP proteins in both ARPKD pathology and lung development and homeostasis. The aim of the study was to determine whether there was a link between non-canonical Wnt signalling and the PKHD1 mutation that was responsible for lung hypoplasia seen in ARPKD patients. Both lung tissue samples from 9-month-old Pkhd1T36M/T36M mice and A549 cells were used in this study. Key proteins from both canonical and non-canonical Wnt pathways were quantified by Western blotting to determine the primary intercellular Wnt signalling pathway associated with lung hypoplasia in ARPKD mutant mouse lungs. Following this, WNT4 and ATMIN single and double knockdowns, as well as WNT11 and PKD2 single and double knockdowns, were performed in A549 cells to assess the interrelationship between these genes and to determine their functional effects in lung epithelial cells. Several cellular functions, including apoptosis, proliferation, adhesion, migration, cell morphology, and actin cytoskeleton expression and localization, were examined. Studies on mouse lungs indicated that the PCP pathway was the primary pathway affected in Pkhd1-mutated mouse lungs, with observed changes in the protein expression of Vangl2 and Scribble. Meanwhile, studies on human lung cell lines suggested that WNT4, ATMIN, WNT11, and PKD2 could be potential regulators of lung development, particularly in branching morphogenesis, alveolar development, and angiogenesis. These findings suggested a contribution to the development of pulmonary hypoplasia in ARPKD patients, in contrast to the initial theory that pulmonary hypoplasia was a secondary effect of cystic and enlarged kidneys. Further investigations will be required to determine the direct involvement of Pkhd1 in lung development. If confirmed, these findings could aid in the development of effective diagnostic tools and therapeutic targets for pulmonary hypoplasia in ARPKD patients.","abstract_has_math":false,"creators":["Aravindan, Raaghavi"],"institution":"University of Wolverhampton","degree_name":"MPhil","degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Goggolidou, Paraskevi"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025","date_published":"2025","updated_at":"2026-07-24T06:10:16Z","subjects":["ARPKD","autosomal recessive polycystic kidney disease","PKHD1","pulmonary hypoplasia","WNT signalling","PCP pathway","A549 cell line"],"languages":[],"rights":[],"rights_urls":["https://wlv.openrepository.com/bitstreams/84d6d290-7f54-4628-8ac8-2e0eeef5f655/download"],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Goggolidou, Paraskevi"]},{"key":"dc:creator","label":"Author","values":["Aravindan, Raaghavi"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Wolverhampton"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://wlv.openrepository.com/handle/2436/626006"]},{"key":"dc:type","label":"Dc Type","values":["Thesis or dissertation"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["MPhil"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["ARPKD","autosomal recessive polycystic kidney disease","PKHD1","pulmonary hypoplasia","WNT signalling","PCP pathway","A549 cell line"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["https://wlv.openrepository.com/bitstreams/84d6d290-7f54-4628-8ac8-2e0eeef5f655/download"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://wlv.openrepository.com/bitstreams/bde70e09-77de-49b9-bb0f-ac1566fc5aef/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Autosomal recessive polycystic kidney disease (ARPKD) is a rare hereditary condition that has been reported to affect approximately one in every 20,000 newborns worldwide. It is caused by a mutation in PKHD1, the gene encoding the protein Fibrocystin (FPC). The primary pathophysiology of ARPKD has been characterized by cystic kidney disease, liver fibrosis, and lung failure. The most severe cases of ARPKD have been observed in neonatal life, with a mortality rate of 30–40%, where the cause of death has been attributed to respiratory distress resulting from lung hypoplasia. If this stage is survived, the chances of long-term survival have been noted to increase to 80%. The specific etiology of this hypoplasia has remained unknown; however, it has been linked to kidney enlargement and oligohydramnios. As a branch of non-canonical WNT signalling, the planar cell polarity (PCP) pathway has emerged as a key ciliary signalling mechanism. Recent studies have highlighted the involvement of core PCP proteins in both ARPKD pathology and lung development and homeostasis. The aim of the study was to determine whether there was a link between non-canonical Wnt signalling and the PKHD1 mutation that was responsible for lung hypoplasia seen in ARPKD patients. Both lung tissue samples from 9-month-old Pkhd1T36M/T36M mice and A549 cells were used in this study. Key proteins from both canonical and non-canonical Wnt pathways were quantified by Western blotting to determine the primary intercellular Wnt signalling pathway associated with lung hypoplasia in ARPKD mutant mouse lungs. Following this, WNT4 and ATMIN single and double knockdowns, as well as WNT11 and PKD2 single and double knockdowns, were performed in A549 cells to assess the interrelationship between these genes and to determine their functional effects in lung epithelial cells. Several cellular functions, including apoptosis, proliferation, adhesion, migration, cell morphology, and actin cytoskeleton expression and localization, were examined. Studies on mouse lungs indicated that the PCP pathway was the primary pathway affected in Pkhd1-mutated mouse lungs, with observed changes in the protein expression of Vangl2 and Scribble. Meanwhile, studies on human lung cell lines suggested that WNT4, ATMIN, WNT11, and PKD2 could be potential regulators of lung development, particularly in branching morphogenesis, alveolar development, and angiogenesis. These findings suggested a contribution to the development of pulmonary hypoplasia in ARPKD patients, in contrast to the initial theory that pulmonary hypoplasia was a secondary effect of cystic and enlarged kidneys. Further investigations will be required to determine the direct involvement of Pkhd1 in lung development. If confirmed, these findings could aid in the development of effective diagnostic tools and therapeutic targets for pulmonary hypoplasia in ARPKD patients."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["ebc8ee23da599633d509551d7aa6d89a","b3488930a79f38e28dfd723adbd17a83","79cc9c558089c2829a28510d0296eb06"]},{"key":"dc:title","label":"Title","values":["Investigating WNT signalling in the lung"]}]}],"canonical_facts":{"dc:contributor.advisor":["Goggolidou, Paraskevi"],"dc:creator":["Aravindan, Raaghavi"],"dc:date.issued":["2025"],"dc:description.abstract":["Autosomal recessive polycystic kidney disease (ARPKD) is a rare hereditary condition that has been reported to affect approximately one in every 20,000 newborns worldwide. It is caused by a mutation in PKHD1, the gene encoding the protein Fibrocystin (FPC). The primary pathophysiology of ARPKD has been characterized by cystic kidney disease, liver fibrosis, and lung failure. The most severe cases of ARPKD have been observed in neonatal life, with a mortality rate of 30–40%, where the cause of death has been attributed to respiratory distress resulting from lung hypoplasia. If this stage is survived, the chances of long-term survival have been noted to increase to 80%. The specific etiology of this hypoplasia has remained unknown; however, it has been linked to kidney enlargement and oligohydramnios. As a branch of non-canonical WNT signalling, the planar cell polarity (PCP) pathway has emerged as a key ciliary signalling mechanism. Recent studies have highlighted the involvement of core PCP proteins in both ARPKD pathology and lung development and homeostasis. The aim of the study was to determine whether there was a link between non-canonical Wnt signalling and the PKHD1 mutation that was responsible for lung hypoplasia seen in ARPKD patients. Both lung tissue samples from 9-month-old Pkhd1T36M/T36M mice and A549 cells were used in this study. Key proteins from both canonical and non-canonical Wnt pathways were quantified by Western blotting to determine the primary intercellular Wnt signalling pathway associated with lung hypoplasia in ARPKD mutant mouse lungs. Following this, WNT4 and ATMIN single and double knockdowns, as well as WNT11 and PKD2 single and double knockdowns, were performed in A549 cells to assess the interrelationship between these genes and to determine their functional effects in lung epithelial cells. Several cellular functions, including apoptosis, proliferation, adhesion, migration, cell morphology, and actin cytoskeleton expression and localization, were examined. Studies on mouse lungs indicated that the PCP pathway was the primary pathway affected in Pkhd1-mutated mouse lungs, with observed changes in the protein expression of Vangl2 and Scribble. Meanwhile, studies on human lung cell lines suggested that WNT4, ATMIN, WNT11, and PKD2 could be potential regulators of lung development, particularly in branching morphogenesis, alveolar development, and angiogenesis. These findings suggested a contribution to the development of pulmonary hypoplasia in ARPKD patients, in contrast to the initial theory that pulmonary hypoplasia was a secondary effect of cystic and enlarged kidneys. Further investigations will be required to determine the direct involvement of Pkhd1 in lung development. If confirmed, these findings could aid in the development of effective diagnostic tools and therapeutic targets for pulmonary hypoplasia in ARPKD patients."],"dc:format.checksum.md5":["ebc8ee23da599633d509551d7aa6d89a","b3488930a79f38e28dfd723adbd17a83","79cc9c558089c2829a28510d0296eb06"],"dc:identifier.uri":["https://wlv.openrepository.com/bitstreams/bde70e09-77de-49b9-bb0f-ac1566fc5aef/download"],"dc:publisher.institution":["University of Wolverhampton"],"dc:relation.isreferencedby":["https://wlv.openrepository.com/handle/2436/626006"],"dc:rights":["https://wlv.openrepository.com/bitstreams/84d6d290-7f54-4628-8ac8-2e0eeef5f655/download"],"dc:subject":["ARPKD","autosomal recessive polycystic kidney disease","PKHD1","pulmonary hypoplasia","WNT signalling","PCP pathway","A549 cell line"],"dc:title":["Investigating WNT signalling in the lung"],"dc:type":["Thesis or dissertation"],"dc:type.qualificationname":["MPhil"]},"updated_at":"2026-07-24T06:10:16Z"}