Enteric neurochemical plasticity and its modulation for future personalized treatment for enteric neuropathies

About This Grant

PROJECT SUMMARY Enteric neuropathies are serious conditions caused by abnormalities in the enteric nervous system (ENS), an extensive neural network that spans the entire gastrointestinal tract and controls gut functions. Reduction in number of neuronal nitric oxide synthesis (nNOS) expressing enteric neurons is a hallmark of many human gastrointestinal diseases, including esophageal achalasia, gastroparesis, and Chagas disease. Despite the prevalence of these conditions and the morbidity they cause, current treatment options are significantly limited and do not directly address the underlying pathophysiology. Cell therapy represents a novel, curative approach to alleviating enteric neuropathies by replacing the absent or injured neurons. Although we have achieved significant successes in our preclinical cell therapy studies using animal models of enteric neuropathy, an enteric neural cell therapy approach specifically tailored for nNOS-deficient diseases would be a significant advance. Recent studies, and our own preliminary experiments, have demonstrated that enteric neural stem cells (ENSCs) generate two neuronal classes that subsequently differentiate into specific phenotypes and that this process includes phenotype switching. This led us to hypothesize that manipulation of this enteric neurochemical plasticity (ENCP) would allow us to optimize ENSC therapy by generating therapeutically relevant, disease- specific neuron subtypes. By utilizing optimized ENSC culture conditions, cell transplantation techniques, transcriptomic analysis, and genetic manipulation, we propose to test our hypothesis that enteric neuronal subtype plasticity occurs postnatally and can be leveraged for cell therapy application. We will also elucidate the role of the transcription factors, Pbx3 and Tbx3 in postnatal ENCP. The proposed studies will advance our understanding of the mechanisms underlying cell commitment in the ENS and how this knowledge could be leveraged to optimize the therapeutic efficacy of cell therapy applications in the future.