At Ace Therapeutics, we specialize in the development of guanylate cyclase-C (GC-C) agonists, offering comprehensive services designed to advance the development of therapeutics for gastrointestinal diseases. With a deep understanding of GC-C signaling pathways and their therapeutic potential, we support the development of GC-C agonists to regulate fluid and electrolyte balance in the gastrointestinal tract.
The Role of Guanylate Cyclase-C in Gastrointestinal Diseases
Guanylate cyclase-C, located in the gastrointestinal tract, regulates fluid and electrolyte balance by producing cGMP in response to guanylin, uroguanylin, and bacterial enterotoxins. This pathway is crucial for intestinal barrier function and fluid absorption. Inhibition of GC-C activity is associated with gastrointestinal diseases such as chronic constipation and irritable bowel syndrome with constipation (IBS-C). GC-C agonists, such as linaclotide and plecanatide, have been approved for the treatment of these conditions, highlighting the potential of GC-C as a drug target.
Figure 1. Salmonella-infected GC-C knockout mice showed a significant reduction in the major secretion of mucin in the intestines. (Amarachintha S., et al., 2018)
What Can We Do for the Development of GC-C Agonists?
- Assays of GC-C knockdown by shRNA
We utilize shRNA technology to knockdown GC-C expression in intestinal epithelial cells and assess the effect on bacterial adhesion and invasion, providing insights into the role of GC-C in host defense against pathogens.
Our approach involves the use of advanced biochemical techniques to quantify cyclic GMP (cGMP) production, the primary product of GC-C activation. We utilize highly sensitive and specific assays, such as enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), to detect cGMP levels in cell and tissue samples. We also offer fluorescence-based methods and high-performance liquid chromatography (HPLC) for precise measurements.
- Host-Pathogen Interaction Studies
We utilize in vitro assays to evaluate the effects of GC-C agonists on the adhesion and invasion of pathogenic bacteria, such as E. coli and Salmonella, into intestinal epithelial cells. This helps assess the potential of GC-C agonists to modulate the host-pathogen interaction and reduce infection risk.
- Mucosal Barrier Assessments
Intestinal Permeability Assays
We employ assays, such as the FITC-dextran permeability assay, to assess the integrity of the intestinal epithelial barrier and to evaluate the effects of GC-C agonists on barrier function.
Tight Junction Protein Expression Analysis
We utilize techniques such as WB and immunofluorescence staining to assess the expression levels of tight junction proteins, such as ZO-1 and occludin in intestinal epithelial cells, providing insights into the effects of GC-C agonists on barrier integrity.
Cytokine Release Assays
We conduct assays to measure the release of inflammatory cytokines, such as TNF-α and IL-6, from intestinal epithelial cells in response to bacterial challenge, assessing the impact of GC-C agonists on the inflammatory response.
In Vivo Models of Inflammation
We employ animal models of intestinal inflammation, such as the dextran sulfate sodium (DSS)-induced colitis mouse models, to assess the ability of GC-C agonists to reduce inflammation and improve disease severity.
By offering these comprehensive services, Ace Therapeutics supports the development and characterization of GC-C agonists, helping to elucidate their therapeutic potential and mechanisms of action. Contact us today to discuss how our expertise can advance your GC-C agonist development for better outcomes in gastrointestinal health.
References
- Amarachintha S., et al. Guanylate cyclase C reduces invasion of intestinal epithelial cells by bacterial pathogens. Sci Rep. 2018, 8(1):1521.
- Waldman S.A., Camilleri M. Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders. Gut. 2018, 67(8):1543-1552.
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