Advisor: Leslie W. Chan, Ph.D.    (Biomedical Engineering, Georgia Institute of Technology & Emory)

Committee:

M.G. Finn, Ph.D.                              (Chemistry and Biochemistry, Georgia Institute of Technology)

Andrés J. García, Ph.D.                   (Mechanical Engineering, Georgia Institute of Technology)

Rheinallt M. Jones, Ph.D.              (Pediatrics, Emory)

Gabe A. Kwong, Ph.D.                     (Biomedical Engineering, Georgia Institute of Technology & Emory)

Engineering Ingestible Probes for Breath-based Detection of Gastrointestinal Diseases

Gastrointestinal (GI) diseases are a significant healthcare burden and affect 70 million people in the United States. Endoscopic imaging plays a crucial role in the diagnosis and clinical management of many GI diseases, including GI cancers, gastroesophageal reflux disease, and inflammatory bowel disease (IBD). However, its invasive nature deters individuals from recommended testing and hinders its routine use as a monitoring tool. Non-invasive blood and fecal biomarker testing have not superseded endoscopy as the gold standard as they frequently rely on single biomarkers, which offer poor disease specificity compared to diagnostic signatures comprised of multiple biomarkers. Unfortunately, conventional biomarker discovery is an arduous and oftentimes black-box process with many barriers to success. Therefore, this proposal seeks to establish a new paradigm to engineer biomarker signatures de novo for GI disease by leveraging dysregulated glycosidase activities in the GI tract. Thousands of distinct host and microbiome glycosidases catalyze the degradation of carbohydrates and shape the overall intestinal “glycome”. Dysregulated intestinal glycosidase activities contribute to GI pathologies via disruption of host-microbiome interactions, intestinal immunity, and gut barrier function. To harness these activities for breath biomarker production, I will develop a new class of molecular probes that are ingestible and metabolized by pathologic glycosidase activities into volatile reporters that are exhaled and detectable in breath. Probe arrays will be designed so that probes for orthogonal glycosidases are barcoded with volatile reporters of distinct mass (i.e. volatile barcodes). Barcode concentrations in breath will be quantified via mass spectrometry and used to build classifiers of GI disease using machine learning. Altogether, I expect the catalytic processing of barcoded probe arrays by intestinal glycosidases will produce amplified, multiplexed breath signals for detection via simple breath testing. To build this platform, I will establish modular chemistries to synthesize probe arrays (Aim 1), characterize probe pharmacokinetics and breath signals after oral delivery (Aim 2), and develop probe arrays for breath-based detection of GI disease in mouse models of IBD and colorectal cancer (Aim 3).

https://gatech.zoom.us/j/92634639259?pwd=mXOBVUAQ7D7vUWC4nffYOWFZ3G7NOC.1