| dc.description.abstract | Asthma is a chronic respiratory disorder that affects people of all ages. Sex and gender disparity in asthma is recognized and suggests a modulatory role for sex steroids, particularly estrogen. However, there is a dichotomous role of estrogen in airway remodeling, making it unclear whether sex hormones are protective or detrimental in asthma and suggesting a need to explore mechanisms upstream or independent of estrogen. Kisspeptins (Kp) are a novel peptide existing upstream of sex steroids and function as a crucial regulator of puberty. Kp via KISS1R are further implicated in the sex steroid biogenesis via action on the gonadotrophins. Therefore, this research hypothesizes that kisspeptin (Kp)/KISS1R signaling serves this role, thereby regulating airway remodeling and airway hyperresponsiveness (AHR).Airway smooth muscle (ASM) is a key structural cell type that contributes to remodeling in asthma. In the first aim, I report novel data indicating that Kp and KISS1R are expressed in human airways, especially ASM, with lower expression in ASM from women compared with men and lower in patients with asthma compared with people without asthma.
My second aim discusses the functional mechanisms of Kp/KISS1R signaling on majorly proliferation, and in part ECM deposition studies. Proliferation studies show that Kp-10, mitigates PDGF-induced ASM proliferation. Pharmacological inhibition and shRNA knockdown of KISS1R increased basal ASM proliferation, which was further amplified by PDGF. The anti-proliferative effect of Kp-10 in ASM was mediated by inhibition of MAPK/ERK/Akt pathways, with altered expression of PCNA, C/EBP-α, Ki-67, cyclin D1, and cyclin E leading to cell cycle arrest at G0/G1 phase. ECM studies show that administration of Kp-10 can mitigate PDGF- and TGFβ- induced increase in ECM remodeling gene and protein expression, such as collagens and fibronectins.
To corroborate my in vitro findings, I have further performed in vivo studies utilizing Kp-10 (a cleaved peptide of parent kisspeptin) in mixed allergen-induced mouse models of asthma. I found that Kp-10 was able to mitigate asthma by significantly improving airway structural, morphological and lung function parameters. Overall, I demonstrate the importance of Kp/KISS1R signaling in the ASM as a potential therapeutic avenue to blunt remodeling in asthma. | en_US |
