Intestinal fibrosis or stricture
Crohn’s disease (CD) currently affects around 1.6 million Americans (Crohn’s and Colitis Foundation). Approximately 30-50% of CD patients develop intestinal strictures, which is fibrosis of the intestine. Intestinal stricture often leads to costly hospitalization and surgery. There is no practical way of preventing or treating intestinal fibrosis. Some factors are associated with the development of intestinal fibrosis.
Prof. Koon discovered two novel diagnostic biomarkers and developed three therapeutic agents for stricturing CD (CDS) patients since 2010. He demonstrated the correlation between serum levels of antimicrobial peptides (cathelicidin and elafin) and the risk of intestinal strictures in CD patients. He established a machine-learning algorithm using multiple easy-to-obtain clinical parameters to improve the accuracy for indicating intestinal stricture risk among CD patients. By using RNA-sequencing and proteomics, Prof. Koon discovered multiple stricture-specific targets in the intestine of stricturing CD patients and utilized advanced pharmaceutical technologies to develop orally active drugs for ameliorating intestinal fibrosis. His innovations and inventions were patented and published in peer-reviewed journals.
C. difficile infection
Clostridioides difficile infection (CDI) is a growing threat to the health care system and its patients. CDI causes severe diarrhea and colitis in patients. According to the Center for Disease Control and Prevention (CDC), there are around almost half a million infections in the United States each year. Old age, hospitalization, immunocompromised status, and previous C. difficile exposure are risk factors for CDI. Postmenopausal women are also associated with an increased trend of CDI-related hospitalization, suggesting hormonal influence. Some studies suggest gender differences in CDI disease outcomes. Additionally, about 1/6 of CDI cases will recur in 2-8 weeks. The use of standard antibiotics is associated with a high relapse rate. Fecal microbiota transplantation (FMT) has a 90% success rate, but cases with severe adverse effects were reported. As current therapeutic options are not ideal, optimization is necessary.
Therefore, Prof. Koon utilized high-throughput screening (HTS) to discover cell signaling pathways and metabolomics to discover metabolites that influence the pathological effects of C. difficile toxins. He identified several novel orally active drugs and metabolites that modulate gut microbiota, immune responses, and intestinal epithelial cell survival in infected animals. These reagents can be safely and effectively used alone or with existing therapeutic regimens to inhibit primary infection and prevent recurrence. Dr. Koon also assisted multiple drug companies in elucidating the mechanisms of action of therapeutic drugs.
Obesity and diabetes
The Centers for Disease Control and Prevention (CDC) reported that 8.6% of U.S. adults are diagnosed with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia with a combination of insulin resistance and relative insulin deficiency. Globally, more men are diagnosed with T2DM than women. The development of T2DM involves many factors and is a topic of intense research.
Prof. Koon discovered the roles of antimicrobial peptides (cathelicidin and elafin) in the development of T2DM. Serum levels of elafin are correlated with fasting blood glucose levels and hemoglobin A1c levels in men with T2DM but not women with T2DM. Elafin modulates systemic inflammation and serum exosomal miRNA levels. These factors influence leptin secretion and sensitivity and food intake, leading to a reversal of obesity and hyperglycemia. His discovery is crucial to understand the gender difference of T2DM and the miRNA-cytokine-hormone axis in the development of obesity and T2DM.
Prof. Koon is a professor in UCLA’s Vatche and Tamar Manoukian Division of Digestive Diseases. He received a master’s degree in pharmacology and a PhD in molecular biology at the University of Hong Kong. He then completed his postdoctoral training in gastroenterology at the Beth Israel Deaconess Medical Center of Harvard Medical School in Boston.
Prof. Koon focuses on basic, clinical, and translational research on inflammatory bowel disease (IBD), C. difficile infection, and metabolic diseases. Over the last decade, Prof. Koon has discovered antimicrobial peptides cathelicidin as a serum biomarker for indicating the presence of intestinal strictures in Crohn’s disease (CD) patients and predicting the future clinical activity in IBD patients. Some of his inventions were patented and licensed to a diagnostic company for commercial development.
In recent years, Prof. Koon has established a biobank that consists of blood, serum exosomes, mesenteric and skin adipose tissues, and intestinal tissues from healthy subjects and IBD patients. By utilizing next-generation transcriptome analysis, he identified multiple biomarkers and molecular targets that might be relevant to intestinal fibrosis. In addition, Prof. Koon developed a convenient machine-learning algorithm for an accurate indication of intestinal strictures in CD patients and discovered the chemical communication between fat and intestine during intestinal fibrosis development.
Prof. Koon is actively involved in developing new therapeutic approaches for gastrointestinal diseases. He utilized an orally active modified cathelicidin mimic CSA13-Eudragit formulation for reversing colitis-associated intestinal fibrosis and C. difficile infection (CDI). His discoveries were published in Scientific Reports and Gastroenterology. Oral administration of CSA13-Eudragit ameliorates intestinal inflammation via modulation of the intestinal microbiome environment. Through untargeted metabolomics studies, he identified several orally active therapeutic metabolites effective against intestinal fibrosis and CDI.
In recent years, Prof. Koon has been collaborating with multiple pharmaceutical companies in drug development. He utilized whole-transcriptome RNA sequencing and multiplex assays to discover molecular targets in C. difficile infection (CDI). For example, he identified that macrophage inflammatory protein-1 alpha (MIP-1a) is a common CDI mediator among humans and mice. Furthermore, MIP-1a specifically mediates inflammatory responses and diarrhea during CDI. Therefore, this immunological discovery helps evaluate disease activity in CDI as well as therapy development against CDI.
Prof. Koon was the first to discover the role of antimicrobial peptides (cathelicidin and elafin) in obesity and prediabetes, and type II diabetes. He observed abnormal levels of serum cathelicidin and elafin in patients with prediabetes and type II diabetes. Cathelicidin regulates obesity and non-alcoholic fatty liver disease (NAFLD) in high-fat diet-treated mice via the reduction of CD36 expression. Recently, Prof. Koon generated an orally active modified elafin formulation for influencing miRNA load in serum exosomes. As a result, the serum exosomes carry miRNAs that improve leptin sensitivity and increase leptin expression, leading to reduced food intake. As a result, the reduced food intake suppression subsequently ameliorates obesity, hyperglycemia, and liver steatosis in high-fat diet-treated mice.
Prof. Koon has published 44 peer-reviewed manuscripts. Prof. Koon’s projects have been funded by CCF, NIH, Broad Foundation and industrial funding. His research team consists of a postdoctoral researcher, a medical resident, a technician and several undergraduate research students. His laboratory, at the MacDonald Research Laboratories building, is a hub of researcher interactions. Prof. Koon’s team develops advanced research platforms such as 3D organoid and ex-vivo cultures, high-throughput screening, microbiota, and immune systems manipulation. Prof. Koon’s research provides an integrated view of interactions between different systems. He welcomes research collaborations for discovering solutions for gastrointestinal and metabolic diseases.
Prof. Koon has 44+ peer-reviewed publications, reviews and book chapters. Click here for complete list