Investigating the role of the extracellular calcium-sensing receptor, CaSR, in the pathogenesis of asthma using surrogate disease models

Huang, Ping 2024. Investigating the role of the extracellular calcium-sensing receptor, CaSR, in the pathogenesis of asthma using surrogate disease models. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Asthma is a prevalent chronic respiratory inflammatory disease, affecting over 300 million people worldwide. There is no curable treatment for asthma. The most common existing combination therapies, inhaled corticosteroids (ICS) and bronchodilators, can only control the symptoms without addressing the underlying cause of asthma and present significant side effects. In addition, asthma is still poorly controlled in many patients even when taking systemic corticosteroids, for instance, in subjects affected by steroid-resistant asthma. Despite the existing unmet medical need, new small-molecule drugs have not been introduced for asthma treatment for the last four decades. The development of biologics in recent years targeting Immunoglobulin E (IgE) or asthma-related cytokines interleukin-4 (IL-4), IL-5 and IL-13, represents potentially novel and effective treatments for asthma. However, biologics are only effective in a subset of patients, due to the difficulty in identifying the targetable patients, and their cost limits for the usages. So, there is a need for the development of more effective, cheaper, small-molecule drugs for asthma, particularly for severe, steroid-resistant asthma management and prevention. During my PhD, I set out to further elucidate the pathogenesis of asthma, and to search potential drugs for asthma patients, especially for severe, steroid-resistant asthmatics, who have limited available treatment options to control their disease. My laboratory has previously shown the widespread expression of calcium-sensing receptor (CaSR), a G-Protein-coupled receptor (GPCR), in human and mouse airways, and its involvement in asthma pathogenesis (Yarova et al, 2015). Our group has also shown that administration of its negative allosteric modulators of the CaSR (CaSR NAMs, also termed calcilytics), delivered to the lung via inhalation, can reduce both airway hyperresponsiveness (AHR) and airway inflammation in murine asthma surrogates, suggesting that inhaled calcilytics may represent a potential therapeutic for asthma. So the aims of my PhD were: 1. To select the best available calcilytic amongst those initially developed for a different use for asthma treatment in an inhaled form; 2. To compare the efficacy of inhaled calcilytic with the current standard-of-care (SoC), inhaled fluticasone propionate (FP), and 3. To test the efficacy of inhaled calcilytic in a classic Th2 asthma model induced by ovalbumin (OVA) and alarmin-driven asthma model induced by IL-33, which may contribute to the pathogenesis of severe, steroid-resistant asthma.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	24 March 2025
Date of Acceptance:	24 March 2025
Last Modified:	24 Mar 2025 15:02
URI:	https://orca.cardiff.ac.uk/id/eprint/177113

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