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Pharmacologic Targeting of the NLRP3 Inflammasome
Pharmacologic Targeting of the NLRP3 Inflammasome
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151433
- ISBN
- 9798382837819
- DDC
- 574
- 서명/저자
- Pharmacologic Targeting of the NLRP3 Inflammasome
- 발행사항
- [Sl] : The Scripps Research Institute, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 141 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-12, Section: B.
- 주기사항
- Advisor: Wiseman, R. Luke;Bollong, Michael J.
- 학위논문주기
- Thesis (Ph.D.)--The Scripps Research Institute, 2024.
- 초록/해제
- 요약The NLRP3 inflammasome is an important innate immune protein complex responsible for regulating the secretion of pro-inflammatory cytokines in response to danger and pathogen associated molecular patterns. Because NLRP3 responds to a diverse array of signals, it is the inflammasome most frequently associated with sterile inflammation in disease such as rheumatoid arthritis or gout. To activate the NLRP3 inflammasome, components are first expressed via NF-κB dependent priming, and then an activating signal causes a conformational change of NLRP3, potentiating oligomerization and ASC binding. This provides a scaffold for caspase-1 activation which functions to cleave IL-1β and IL-18 to their active forms for secretion. As inflammation induced by the NLRP3 inflammasome contributes to the negative pathology of many diseases, inhibitors of the NLRP3 inflammasome are highly desirable. There are several NLRP3 inflammasome inhibitors in clinical trials, yet thus far no inhibitors have been approved. These established inhibitors generally work through a conserved mechanism of binding the NLRP3 nucleotide binding domain and inhibiting ATPase activity. However, because of the array of signals that NLRP3 responds to, there are likely other mechanisms that can be used to inhibit NLRP3 which may perform more favorably in the clinic. In this dissertation, we present a high throughput screen for novel NLRP3 inflammasome inhibitors, from which we identify covalent modification of numerous cysteines as a conserved mechanism for inflammasome inhibition. This suggests that NLRP3 serves as an electrophile sensor in the cell to regulation inflammation (Chapter 1). Similar to the known electrophile sensor KEAP1, which regulates the NRF2 oxidative stress response, we posited that NLRP3 is also likely sensitive to covalent modification by reactive metabolites. To expand upon this idea, we show that methylglyoxal, a reactive metabolite originating from glycolysis, covalently modifies and inhibits NLRP3 via a crosslinking MICA modification (Chapter 2). These studies provide new insight into the regulation of NLRP3 and the potential for the development of dual NRF2-activating, NLRP3-inhibiting covalent drug molecules. Additionally, while overactivity of the NLRP3 inflammasome is frequently detrimental, inflammasome agonists have the potential for use as immune stimulating adjuvants in vaccines. Despite this utility, there are almost no published direct inflammasome agonists. In this dissertation, we identify two novel inflammasome agonists which induce IL-1β secretion through presumably two different inflammasomes (Chapter 3). These molecules provide useful tools for the development of more effective adjuvants and may mechanistically reveal more about the regulation of different inflammasomes.
- 일반주제명
- Cellular biology
- 일반주제명
- Chemistry
- 일반주제명
- Pharmacology
- 일반주제명
- Molecular biology
- 일반주제명
- Immunology
- 키워드
- Inflammasome
- 키워드
- Metabolism
- 키워드
- NLRP3
- 기타저자
- The Scripps Research Institute Chemical Biology
- 기본자료저록
- Dissertations Abstracts International. 85-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211151433
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■020 ▼a9798382837819
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aStanton, Caroline Rose.
■24510▼aPharmacologic Targeting of the NLRP3 Inflammasome
■260 ▼a[Sl]▼bThe Scripps Research Institute▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a141 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-12, Section: B.
■500 ▼aAdvisor: Wiseman, R. Luke;Bollong, Michael J.
■5021 ▼aThesis (Ph.D.)--The Scripps Research Institute, 2024.
■520 ▼aThe NLRP3 inflammasome is an important innate immune protein complex responsible for regulating the secretion of pro-inflammatory cytokines in response to danger and pathogen associated molecular patterns. Because NLRP3 responds to a diverse array of signals, it is the inflammasome most frequently associated with sterile inflammation in disease such as rheumatoid arthritis or gout. To activate the NLRP3 inflammasome, components are first expressed via NF-κB dependent priming, and then an activating signal causes a conformational change of NLRP3, potentiating oligomerization and ASC binding. This provides a scaffold for caspase-1 activation which functions to cleave IL-1β and IL-18 to their active forms for secretion. As inflammation induced by the NLRP3 inflammasome contributes to the negative pathology of many diseases, inhibitors of the NLRP3 inflammasome are highly desirable. There are several NLRP3 inflammasome inhibitors in clinical trials, yet thus far no inhibitors have been approved. These established inhibitors generally work through a conserved mechanism of binding the NLRP3 nucleotide binding domain and inhibiting ATPase activity. However, because of the array of signals that NLRP3 responds to, there are likely other mechanisms that can be used to inhibit NLRP3 which may perform more favorably in the clinic. In this dissertation, we present a high throughput screen for novel NLRP3 inflammasome inhibitors, from which we identify covalent modification of numerous cysteines as a conserved mechanism for inflammasome inhibition. This suggests that NLRP3 serves as an electrophile sensor in the cell to regulation inflammation (Chapter 1). Similar to the known electrophile sensor KEAP1, which regulates the NRF2 oxidative stress response, we posited that NLRP3 is also likely sensitive to covalent modification by reactive metabolites. To expand upon this idea, we show that methylglyoxal, a reactive metabolite originating from glycolysis, covalently modifies and inhibits NLRP3 via a crosslinking MICA modification (Chapter 2). These studies provide new insight into the regulation of NLRP3 and the potential for the development of dual NRF2-activating, NLRP3-inhibiting covalent drug molecules. Additionally, while overactivity of the NLRP3 inflammasome is frequently detrimental, inflammasome agonists have the potential for use as immune stimulating adjuvants in vaccines. Despite this utility, there are almost no published direct inflammasome agonists. In this dissertation, we identify two novel inflammasome agonists which induce IL-1β secretion through presumably two different inflammasomes (Chapter 3). These molecules provide useful tools for the development of more effective adjuvants and may mechanistically reveal more about the regulation of different inflammasomes.
■590 ▼aSchool code: 1179.
■650 4▼aCellular biology
■650 4▼aChemistry
■650 4▼aPharmacology
■650 4▼aMolecular biology
■650 4▼aImmunology
■653 ▼aCovalent modification
■653 ▼aElectrophile sensor
■653 ▼aInflammasome
■653 ▼aMetabolism
■653 ▼aNLRP3
■690 ▼a0379
■690 ▼a0485
■690 ▼a0982
■690 ▼a0419
■690 ▼a0307
■71020▼aThe Scripps Research Institute▼bChemical Biology.
■7730 ▼tDissertations Abstracts International▼g85-12B.
■790 ▼a1179
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17161703▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
