東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

FindBook

Google Book

Amazon

博客來

Development and Testing of a Novel Humanized Protease-Activated-Receptor-2 Mouse as a Model for Allergic Asthma.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Development and Testing of a Novel Humanized Protease-Activated-Receptor-2 Mouse as a Model for Allergic Asthma./
作者:	Gillman, Samuel.
面頁冊數:	1 online resource (109 pages)
附註:	Source: Masters Abstracts International, Volume: 84-12.
Contained By:	Masters Abstracts International84-12.
標題:	Physiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30489369click for full text (PQDT)
ISBN:	9798379593537

Development and Testing of a Novel Humanized Protease-Activated-Receptor-2 Mouse as a Model for Allergic Asthma.
Gillman, Samuel.

Development and Testing of a Novel Humanized Protease-Activated-Receptor-2 Mouse as a Model for Allergic Asthma. - 1 online resource (109 pages)

Source: Masters Abstracts International, Volume: 84-12.

Thesis (M.S.)--The University of Arizona, 2023.

Includes bibliographical references

Allergic asthma, the most common form of asthma, is characterized by airway inflammation, mucus overproduction, leukocyte infiltration, and airway hyperresponsiveness (AHR). Allergic asthma can be triggered by allergen exposure, which includes house dust mites (HDM) and Alternaria alternata (A.alternara). Protease-activated-receptor-2 (PAR2) activation by HDM and A. alternata has been linked to the development of asthma indicators in preclinical models. Despite the critical role of PAR2 in allergic asthma, limited research has been conducted on targeting PAR2 in treating allergic asthma, all of which has been performed on mice expressing the murine receptor (mPAR2). In this thesis, I address this gap in research with the development of a transgenic mouse model expressing only the human form of PAR2 (hTgPAR2) devoid of mouse PAR2 in a C57Bl/6 background. Both hTgPAR2 and C57Bl/6 mice responded to acute HDM challenge with increased airway inflammation, mucus production, and leukocyte migration with limited sex differences. However, the hTgPAR2 mouse presented with significantly increased AHR in response to HDM exposure in both male and female mice, whereas the C57Bl/6 mice displayed no difference from control. We have shown that A. alternata can induce allergen indicators in pre-clinical mouse models and that these indicators can be pharmacologically controlled by a full (e.g., Gq/Ca2+ and β-arrestin-2/MAPK signaling) PAR2 antagonist (C391) or a biased β-arrestin-2/MAPK signaling (C781) PAR2 antagonist. As with C57Bl/6 and BALB/c mouse strains, acute A. alternata exposure induced AHR, increased inflammation, and mucus production in hTgPAR2 mice. However, clear sex differences were observed with the male hTgPAR2 mice driving the increased AHR and female hTgPAR2 mice driving heightened inflammation and mucus production. When tested in hTgPAR2 mice, the biased PAR2 antagonist, C781, demonstrated greater efficacy in controlling AHR induced by A. alternata than C391. Lastly, two new PAR2 antagonists, C937 and C938 possess improved pharmacokinetics and are shown to be biased PAR2 antagonists in in vitro studies, selectively limiting the β-arrestin-2/MAPK signaling pathway. Overall, my findings suggest that the hTgPAR2 mouse may serve as a model for allergic asthma and as an in vivo tool for evaluating PAR2 antagonists in the treatment of allergic asthma, with biased PAR2-β-arrestin-2/MAPK antagonists such as C781 appearing to be a promising therapeutic approach.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798379593537Subjects--Topical Terms:

518431
Physiology.
Subjects--Index Terms:

AsthmaIndex Terms--Genre/Form:

542853
Electronic books.

Development and Testing of a Novel Humanized Protease-Activated-Receptor-2 Mouse as a Model for Allergic Asthma.
LDR:03892nmm a2200397K 4500 001 2363962
005 20231127094746.5
006 m o d
007 cr mn ---uuuuu
008 241011s2023 xx obm 000 0 eng d
020 $a 9798379593537
035 $a (MiAaPQ)AAI30489369
035 $a AAI30489369
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Gillman, Samuel. $3 3704741
245 1 0 $a Development and Testing of a Novel Humanized Protease-Activated-Receptor-2 Mouse as a Model for Allergic Asthma.
264 0 $c 2023
300 $a 1 online resource (109 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Masters Abstracts International, Volume: 84-12.
500 $a Advisor: Boitano, Scott.
502 $a Thesis (M.S.)--The University of Arizona, 2023.
504 $a Includes bibliographical references
520 $a Allergic asthma, the most common form of asthma, is characterized by airway inflammation, mucus overproduction, leukocyte infiltration, and airway hyperresponsiveness (AHR). Allergic asthma can be triggered by allergen exposure, which includes house dust mites (HDM) and Alternaria alternata (A.alternara). Protease-activated-receptor-2 (PAR2) activation by HDM and A. alternata has been linked to the development of asthma indicators in preclinical models. Despite the critical role of PAR2 in allergic asthma, limited research has been conducted on targeting PAR2 in treating allergic asthma, all of which has been performed on mice expressing the murine receptor (mPAR2). In this thesis, I address this gap in research with the development of a transgenic mouse model expressing only the human form of PAR2 (hTgPAR2) devoid of mouse PAR2 in a C57Bl/6 background. Both hTgPAR2 and C57Bl/6 mice responded to acute HDM challenge with increased airway inflammation, mucus production, and leukocyte migration with limited sex differences. However, the hTgPAR2 mouse presented with significantly increased AHR in response to HDM exposure in both male and female mice, whereas the C57Bl/6 mice displayed no difference from control. We have shown that A. alternata can induce allergen indicators in pre-clinical mouse models and that these indicators can be pharmacologically controlled by a full (e.g., Gq/Ca2+ and β-arrestin-2/MAPK signaling) PAR2 antagonist (C391) or a biased β-arrestin-2/MAPK signaling (C781) PAR2 antagonist. As with C57Bl/6 and BALB/c mouse strains, acute A. alternata exposure induced AHR, increased inflammation, and mucus production in hTgPAR2 mice. However, clear sex differences were observed with the male hTgPAR2 mice driving the increased AHR and female hTgPAR2 mice driving heightened inflammation and mucus production. When tested in hTgPAR2 mice, the biased PAR2 antagonist, C781, demonstrated greater efficacy in controlling AHR induced by A. alternata than C391. Lastly, two new PAR2 antagonists, C937 and C938 possess improved pharmacokinetics and are shown to be biased PAR2 antagonists in in vitro studies, selectively limiting the β-arrestin-2/MAPK signaling pathway. Overall, my findings suggest that the hTgPAR2 mouse may serve as a model for allergic asthma and as an in vivo tool for evaluating PAR2 antagonists in the treatment of allergic asthma, with biased PAR2-β-arrestin-2/MAPK antagonists such as C781 appearing to be a promising therapeutic approach.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2023
538 $a Mode of access: World Wide Web
650 4 $a Physiology. $3 518431
650 4 $a Pharmacology. $3 634543
650 4 $a Immunology. $3 611031
653 $a Asthma
653 $a Airway inflammation
653 $a Leukocyte infiltration
653 $a Murine receptor
653 $a Therapeutic approach
655 7 $a Electronic books. $2 lcsh $3 542853
690 $a 0719
690 $a 0982
690 $a 0419
710 2 $a ProQuest Information and Learning Co. $3 783688
710 2 $a The University of Arizona. $b Physiological Sciences. $3 1023472
773 0 $t Masters Abstracts International $g 84-12.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30489369 $z click for full text (PQDT)