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Finding the Best Animal Model Organisms for Biliary Atresia

 


Biliary atresia (BA) is a congenital condition that a blockage happens in the tubes responsible for carrying bile from the liver to the gallbladder. It results from abnormal development of the bile ducts inside or outside the liver and results in progressive fibrous obliteration with different degrees of inflammation in the hepatobiliary system. According to incomplete statistics, about 1 out of 10,000–20,000 live births would be identified with biliary atresia, but actually, the situation could be worse given the late diagnoses. Up to now, the causes for this condition remain unclear and seem to be heterogeneous, but it undoubtedly would lead to an inestimable mental and financial burden for patients and their families, as well as the healthcare system.

 

To better understand and identify the etiology of biliary atresia, researchers are dedicated to finding the best animal model organism to verify their hypothesis of viral or genetic etiology. Identification of well-defined animal models will give researchers a chance to look into the complexity of the inflammation degree and the development state of the biliary system in BA, offering insights into the development of new therapeutics.

 

Limitations of Experimental Animal Models for BA

 

Animal models are widely used to investigate the biology and preclinical mechanisms, but models that have not been properly standardized and validated may make it more challenging to understand BA's already complex biologic process. Variables of model organisms that exert an influence on the result of investigation include age, sex, biliary development, metabolic pathways, and microbiome diversity. For instance, some rodent models are ideal for studying various inflammation mechanisms, but they may have shortcomings in translating genetic research data to human terms. Therefore, it's important to be familiar with the limitations and advantages of different animal models, which helps more accurately comprehend the pathophysiological mechanisms of this disease.

 

Different animal model species (both non-human primates and non-primates) have been applied in biliary atresia studies, such as the rat, mice, zebrafish, lamprey, and rhesus monkey, for viral, surgical, toxin-based, and genetic research.

 

Zebrafish as Biliary Atresia Animal Models

 

The zebrafish (Danio rerio) has been increasingly important to scientific research for decades, especially when it comes to characteristics that are valuable for studying human genetics and disease. Thus, this tropical fish native to the Southeast has the potential to be a model for studying biliary defects considering its remarkable conservation of developmental genes. Furthermore, the notch signaling pathway that is essential for mammalian biliary development also plays a key role in regulating the specification of liver progenitor cells towards a biliary cell fate in zebrafish.

 

Lamprey as Biliary Atresia Animal Models

 

The sea lamprey (Petromyzon marinus), native to the northern Atlantic Ocean and freshwater of the Great Lakes, is a primitive fish, whose metamorphosis is a genetically pre-programmed animal model for biliary atresia. Its biliary system is fully formed in the larva stage along with the gallbladder and will be lost during transitioning from the larva to the adult stage. As early as 1978, researchers had found some morphological similarities, including the transformation and expansion of extrahepatic ductal epithelial cells in lamprey larvae stage into the tail of the pancreas in the adult, and the regression of the biliary structures accompanied by periductular fibrosis in the lamprey. The lamprey was recently adapted as an experimental animal model for BA because of the ability to tolerate BA and normally grow to adult size without developing any sort of progressive disease.

 

Rhesus Macaque as Biliary Atresia Animal Models

 

The rhesus macaque (Macaca mulatta) actually is a compromised animal model in that it's close to humans meanwhile feasible for surgical manipulation. Rhesus monkey was the only nonhuman primate identified with pure extrahepatic BA, but later research was significantly limited due to the overthrow of the viral hypothesis in the etiologic study of BA and ethical disapproval.

 

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