Platelet-derived growth factor receptor alpha signaling pathways in development and liver disease
Year: 2014
Type: dissertation
Abstract: Platelet derived growth factor receptor alpha (PDGFRα) signaling is critical for development and disease.Insufficient PDGFRα signal transduction results in developmental anomolies, while excessive signaling results in fibrosis and carcinogenesis.PDGFRα signal transduction is regulated at multiple levels, two of which are ligand binding and Pdgfrα expression levels.In my thesis work, I describe a Pdgfc mutant mouse, Pdgfc tm1Lex , in which only growth factor coding exons are deleted.Viability of Pdgfc tm1Lex mice, which express only the complement components C1r/C1s, sea urchin EGF, bone morphogenetic protein 1 (CUB) domain of PDGF-C, depends on the presence of both Pdgfrα alleles.Alternative splicing in Pdgfc tm1Lex mice gives rise to a truncated transcript that contains the entire coding region of the CUB domain of PDGF-C, but lacks the majority of the exons encoding the growth factor domain (GFD).Contrary to Pdgfc knockout (KO) mice, Pdgfc tm1Lex mice are viable, suggesting that the CUB domain of PDGF-C contributes to PDGFRα signal transduction.The CUB domain of PDGF-C appears to maintain PDGFRα signal transduction above the minimum level necessary for development.At the other end of the spectrum, increased PDGFRα signal transduction can contribute to disease.PDGFRα levels are elevated in human liver disease, and after acute and chronic liver injury in mice.These correlative studies indicate that PDGFRα may be important for the liver's response to injury.Activated hepatic stellate cells (HSCs) produce collagen resulting in fibrosis, which can progress to liver cirrhosis.Cirrhosis is the 12 th leading cause of death in the United States, and increases the risk of developing liver cancer.Utilizing a chemical model of fibrosis, chronic carbon tetrachloride (CCl 4 ) exposure, I found that mice with decreased expression of Pdgfrα (Pdgfrα WT/nGFP ) develop less fibrosis, than wild type mice following CCl 4 exposure.These results indicate that elevated Pdgfrα expression is associated with chronic liver injury, and suggests excessive PDGFRα signal transduction is detrimental.PDGFRα signal transduction is controlled at the level of ligand binding and gene expression, and needs to be maintained at a balance that allows for proper development, but does not result in fibrotic disease.Therapies targeted to maintain the balance of PDGFRα-specific signaling pathways may provide both sufficient PDGFRα for wound healing and therapeutic benefit for patients with chronic liver disease.
Author: Brian Hayes
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2287293508