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Research from the School of Pharmacy. The website may be found at https://www.ndsu.edu/pharmacy/

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Browsing Pharmacy by Subject "Asthma"

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    Estrogen Receptors Signaling in Airway Smooth Muscles: Role in Intracellular Calcium Regulation and Contractility
    (North Dakota State University, 2021) Sangeeta, Bhallamudi
    Epidemiological evidence suggests higher incidence and severity of asthma in pre-menopausal women and aging men, suggesting a role of sex steroids, especially estrogen. In this regard, it is not clear whether specific estrogen receptors (ERα and ERβ) play differential roles or whether there is any imbalance in their normal signaling during asthma. Airway smooth muscle (ASM) cell is of contractile phenotype which is involved in contractions and airway hyperresponsiveness. Therefore, this research focused to understand ER signaling in the context of airway hyperresponsiveness and bridge the gaps in knowledge about the role of ERs in human ASM cells. The first aim demonstrate the long-term differential signaling of ERs in the regulation of [Ca2+]i handling in the human ASM. It was found that ERα activation increases the [Ca2+]i response in baseline conditions, while ERβ activation has neutral effect. Moreover, the differential signaling of ERs is more evident in asthma or inflammation where ERβ activation decreases the [Ca2+]i response in the presence of inflammation while ERα increases it. Further elucidation of the mechanisms of their signaling on [Ca2+]i suggests that ERβ results in decreased [Ca2+]i response through increased SERCA2 expression and function, inhibition of pathways involved in activating the voltage gated LTCC and maintenance of the morphology of mitochondria. In the next aim, it was found that ERβ causes a potentiation of the activity of β2-AR which leads to an increase in cAMP. Also, ERβ is found to be involved in dephosphorylation of contractile apparatus ultimately leading to bronchodilation. Presenting a contrasting picture, ERα causes an increase in pro-contractile machinery such as RhoA activity and phospho-MYPT leading to increased overall contractility in ASM cells. To confirm these in vitro findings in the presence of other structural and immune cells involved in inflammation, I have further evaluated the ex vivo and in vivo roles of ER signaling in airways. Interestingly, ERβ was found to be protective for the airways while ERα further aggravated the contractility of the airways. These novel findings of ER signaling in the context of contractile mechanisms of the airways can be utilized in designing novel therapeutics for bronchodilation.
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    Kisspeptins: Airway Remodeling in Asthma
    (North Dakota State University, 2022) Borkar, Niyati
    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.