| Summary: | <p>Second messengers play roles in communication between and within cells and are critical in various physiological functions at cellular level. As an important second messenger, Ca2+, through spatiotemporal changes in its cytosolic concentration in the cell, regulates multiple physiological processes. One source of cytosolic Ca2+ is the intracellular Ca2+ stores which mainly include the endoplasmic reticulum (ER) and the endolysosomal system. In past decades, research has identified the different triggers and mechanisms of Ca2+ release from different organelles. NAADP, as the most potent trigger, initiates Ca2+ release from the endolysosomal system, and there is evidence that two pore channels (TPCs), a type of cation channel located in endolysosomes, can mediate such Ca2+ release. Much previous research has successfully investigated the functions of TPCs in various physiological and pathological processes. In my studies, I have employed TPC gene-edited animal and cell models to investigate the function of TPCs in metabolism, particularly adipocyte differentiation, and pancreatic digestive enzyme secretion.</p>
<p>Obesity and related metabolic diseases have become a major problem; in the UK they are estimated to affect around 25% of adults and around 20% of children. Drug treatments with a minimum of adverse reactions could be an important tool alongside preventative measures. TPCs were investigated as a potential target for anti-obesity treatment in two different aspects: adipogenesis and lipid absorption. The studies were based on unpublished evidence that Tpcn1-null mice are leaner with less lipid absorption in the intestine; also, the differentiation from mesenchymal stem cells to adipocytes in a Tpcn2 knock-down cell line is significantly reduced.</p>
<p>In this study I showed that pancreatic acinar cells isolated from Tpcn1-null mice have reduced lipase activity, and also that activities of other pancreatic enzymes are reduced. Moreover, Raman spectroscopy of Tpcn1/2 double-knockout pancreatic acinar cells show a reduction in the abundance of cytochrome C, which is the first study that connects TPCs with cytochrome C and should further lead to understanding of the relationship between TPCs and cell apoptosis. With regard to adipocyte differentiation, a shRNA knock-down mesenchymal stem cell model as well as preadipocytes isolated from Tpcn2-null mice showed reduced adipogenesis and the reduction seems to be led by an alteration in cyclic AMP signalling levels that induces Tpcn2 gene expression with calpain as a downstream modulator. In addition, hepatocytes isolated from Tpcn1-null mice were used as a model for SARS-CoV-2 pseudo-virus infection study, and the results showed that TPC1 may have functions in the infection of senile high-fat diet mice, and TPC1 may be regulating expression of TIMP-1 after infection.</p>
<p>The study of TPCs’ role in lipid metabolism has expanded our understanding of this pathophysiological process and could lead to the identification of new therapeutic drug targets for anti-obesity treatment.</p>
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