Research

Keywords: Cellular responses to stress; DNA damage and repair; Host-microbe interaction; Infection/inflammation-mediated cancer; Innate immune responses to pathogens; Microbial pathogenesis; Gut microbiome; Inflammatory diseases; Gastro-intestinal diseases; Gut barrier and physiology; ‘gut in a dish’ model with microbes, immune and epithelial components; Organoid and stem cell biology; Target identification, validation and drug testing in the organoid based disease model for chronic diseases-including aging, inflammation and cancer.

1. Innate responses following infection with enteric microbes

This project will decipher the differential host responses following interaction with the gut microbiota and pathogenic bacteria in the gastrointestinal tract. Bacterial recognition by the host is fundamental for the initiation of mucosal immune responses. Previously we identified Brain Angiogenesis Inhibitor-1 (BAI1) as a Pattern Recognition Receptor that binds Bacterial Lipopolysaccharide. BAI1 interacts with Engulfment and Cell motility protein 1 (ELMO1) that facilitates bacterial engulfment and intestinal inflammation. Our latest research shows that ELMO1 interacts specifically with a Salmonella effector present only in pathogens and generates differential immune responses after encountering pathogen vs. non-pathogenic commensals. We also observed that ELMO1 interacts with the late endosomal marker and modifies innate immune responses. The central hypothesis is that the cross talk between bacterial effector molecules, ELMO1, and the host endocytic pathway regulates innate immune responses following engulfment. We will focus on how ELMO1 contributes to microbial sensing and inflammation that modulates the endocytic pathway during innate immune responses.

2. Molecular Signature of Infection and Inflammation-driven Colorectal Cancers

Initiation and progression of colorectal polyps to cancers (CRCs) are fueled by genetic, epigenetic and environmental factors. Although inflammation driven by microbes has been postulated, how they may fuel CRCs and which strains are capable remain unknown. Here, a disease map of colon polyps was built in a multi-disciplinary collaboration with cell biologists computer scientists by querying human transcriptomic datasets using unbiased computational approaches. The map revealed that suppression of one of the metabolic master-regulator and its activity is one of the earliest steps in adenoma initiation, whereas an IL8-predominant proinflammatory signature, leakiness, and Wnt-driven EMT/stemness are late events during adenoma initiation and progression. These events were recapitulated when mouse and human enteroid monolayers were infected with anaerobic, CRC-associated bacteria Fusobacterium nucleatum (FN). Analyses of transcriptomic datasets from time-lapse models of polyp-to-CRC and colitis-to-CRC progression showed that the unique set of late events imply a higher risk of progression to CRCs, spurring the name MACS (Microbe-associated CRC-signature). Mechanistically, FN appears to induce MACS, and consequently turning off the specialized tumor-suppressive stress-polarity signaling (SPS)- pathway it orchestrates; pharmacologic activation of the SPS-pathway fortifies epithelial TJs and resists the induction of MACS upon FN infection.

3. Identification of the predictive biomarkers for inflammatory diseases

In a pilot study with UCSD Clinical Trial and Research Institute, we found that in Crohn’s disease (CD) intestinal specimens, ELMO1, and CCL2/MCP-1 (Monocyte Chemoattractant Protein-1) are upregulated. MCP-1 is a potent chemoattractant for monocytes and in inflammatory bowel diseases (IBD). It may promote immune cells to secrete pro-inflammatory mediators and induce chronic intestinal inﬂammation. Infecting the stem cell-based enteroid model (from humans and mice), we will study the role of epithelial-immune cells cross-talk, responsible for inflammation and metabolic diseases.

4. Tightening the Gut Barrier to combat infectious, chronic diseases

The compromised intestinal barrier is associated with chronic diseases such as obesity, diabetes, inflammatory bowel diseases, metabolic endotoxemia and so far there is no clinical treatment for the treatment of barrier loss. After encountering the pathogenic attacks or with the exposure of microbial products or toxic components from the environment, the epithelial tight junctions collapse and promote the diseases. Here we propose the molecular mechanism that protects the host epithelial barrier integrity can be targeted to prevent the progression of chronic diseases (specifically using Inflammatory Bowel Disease as a model).

5. Identification of therapeutic approaches in the treatment of infection/inflammation-associated cancer:

Prediction from publicly available big data analysis showed that inflammation, tight junction proteins, DNA damage-repair pathways, and differentiation-proliferation pathways play a significant role in the progression of gastric and colon cancer. Previously Helicobacter pylori was used as a model of gastric cancer, and the role of DNA repair and the pathways involving host-immune responses were studied.

In collaboration with Drs. Sahoo and Ghosh, the Boolean analysis was carried out in an intent to identify druggable targets that can drive a pro-differentiation program in the colon crypts. Preliminary studies have shown that potent and specific target-agonists do indeed reduce stemness and trigger differentiation, and even induce regression of ex vivo organoid cultures derived from colorectal adenomas and CRCs.

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