Battle Lab - 2022 CMGH Journal Cover

 

Examining Gastrointestinal Diseases Through Developmental Biology

Description of Research

The Battle lab examines digestive diseases through a developmental biology lens. Reactivation of pathways used during embryonic organ development to pattern tissues and specify cell fate and function often plays a role in disease. Therefore, investigating organ development can provide a unique window into the mechanisms of human diseases. Using cutting-edge molecular and cellular biology tools in the context of animal and organoid model systems, we seek to delineate fundamental mechanisms of gastrointestinal epithelial tissue patterning, epithelial cell specification and differentiation, and epithelial tissue morphogenesis. The long-term goal is to apply the knowledge gained to gastrointestinal diseases, including short bowel syndrome, inflammatory bowel disease, metaplasia such as Barrett's esophagus, and cancer.
A simple idea has guided my research approach: the unique assembly of transcription factors present in cells directs organ patterning, cell specification and differentiation, and tissue morphogenesis. Complexity arises with spatiotemporal changes in the transcription factor landscape. My laboratory primarily focuses on how GATA transcription factors, particularly GATA4 and GATA6, regulate gastrointestinal organ development and how alterations in GATA factor function contribute to GI diseases.
Overall, my laboratory has made significant contributions to our understanding of the essential transcriptional and signaling mechanisms regulating the development and function of the GI epithelium and how alterations in these mechanisms may contribute to gastrointestinal diseases, including cancer. We integrate cellular and molecular biology tools to explore fundamental cell functions in healthy and diseased tissues. We envision that the insights we provide about organ development and cell functions will be applicable long-term to identifying screening and therapeutic targets and to regenerative medicine strategies that strive to generate specific GI cell types and tissue-engineered GI organs to replace functions lost in disease or injury.

Current Projects

Examining the role of GATA4 in gastric parietal cell development and disease:
Parietal cells provide essential GI functions, producing and secreting gastric acid for digestion and to kill pathogens. These cells also synthesize growth factors that influence parietal cells themselves and other gastric cell types. Parietal cell dysfunction underlies a range of human diseases associated with a high socioeconomic burden, including chronic gastritis, drug-related peptic ulcer disease, Helicobacter pylori-related peptic ulcer disease, H. pylori-associated gastritis, metaplasia, and cancer. Parietal cell loss is a crucial pathological step in gastric cancer. However, the mechanisms through which parietal cells are specified and maintained and how loss of parietal cells contributes to gastric disease are poorly defined. The idea that GATA family transcription factors regulate parietal cell function was first proposed in 1993. Our lab's new data support an essential role for GATA4 in parietal cells and implicate GATA4 as a crucial principal regulator of parietal cells. We are using mouse and organoid models paired with state-of-the-art techniques to comprehensively and mechanistically define GATA4's role in parietal cell fate/function.

Examining the role of GATA factors in human gastric development:
It is critical to translate what is learned about GATA function in rodent stomachs to a human system to evaluate the degree to which GATA function in gastric biology is conserved among species. Therefore, this project focuses on determining the extent to which GATA function is shared between mice and humans. Gastric organoids generated from human cells offer a model system in which GATA expression can be eliminated or amplified to examine the impact of GATA on parietal cells and overall gastric epithelial cell biology. By applying what we learn via mouse models to human biology, we expect to expand our understanding of the role of GATA factors during human parietal development and potentially in human gastric diseases.

Examining the role of GATA factors in esophageal disease:
We found that GATA4 can elicit switches in the structure of the lining of the esophagus and stomach, suggesting a role for GATA4 in metaplastic diseases. Esophageal metaplasia, known as Barrett's esophagus, occurs when columnar epithelium with gastric and intestinal identity replaces the stratified squamous esophageal epithelium. Individuals with Barrett’s esophagus have an elevated lifetime risk for esophageal adenocarcinoma, a deadly cancer with a less than 20% five-year survival rate. Esophageal cancer is currently the seventh leading cause of cancer-related deaths worldwide and is the fastest growing type of cancer in western countries. Advances toward prevention, diagnosis, and treatments have been limited because the basic mechanisms underlying the progression from normal to cancer are poorly defined. Therefore, we are examining GATA4's role in Barrett’s esophagus and cancer using unique mouse lines generated in our lab. We expect that our novel models will open a new avenue for discovery into the mechanisms of esophageal cancer and provide a model to screen novel esophageal cancer drugs.