Molecular mechanisms and novel biological-based therapies for anthrax lethal toxin-induced mortality
炭疽致命毒素引起的死亡的分子机制和新型生物疗法
基本信息
- 批准号:10246693
- 负责人:
- 金额:$ 51.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAllelesAnimalsAnthrax AttackAnthrax diseaseAntibioticsAntibodiesBacillus anthracisBacterial InfectionsBioenergeticsBiologicalBiological ProcessBioterrorismCardiac MyocytesCaringCell ProliferationCell SurvivalCellsCessation of lifeClinicalClinical ManagementCommunicable DiseasesComplementDataDefense MechanismsDiseaseEpidermal Growth FactorGoalsHumanImpairmentInfectionInhalationMAP Kinase GeneMAP2K1 geneMAPK8 geneMEKsMedicalMedical AssistanceMetabolismMetalloproteasesMitogensMolecularMolecular TargetOrganPathogenesisPathway interactionsPatientsPlayPublic HealthResearchResistanceRoleSeptic ToxemiaStressSymptomsTestingTherapeuticTimeTissuesToxic effectToxinVirulence Factorsanthrax lethal factorantitoxinbasec-myc Genescardiovascular collapseevidence baseexpectationfluin vivomortalitymouse modelnovelp38 Mitogen Activated Protein Kinasepathogenpreventrepairedtargeted treatment
项目摘要
Abstract
Bacillus anthracis, the causative agent of anthrax disease, has remained as a top bioterrorism concern since the
2001 anthrax attack. B. anthracis causes anthrax through a combination of bacterial infection and toxemia. As a
major virulence factor, the anthrax lethal toxin (LT) plays an essential role during multiple steps of the disease.
Due to the rapid course of anthrax disease, in particular, the non-specific, flu-like symptoms of inhalational
anthrax, patients usually seek medical assistance when the disease is already in the middle/late stages, making
the clinical management of anthrax patients an extremely challenging task. Current treatments include antibiotics
and anti-toxin antibodies that respectively eliminate the pathogen and neutralize the toxin. However, there is no
therapy available to deal with the cellular/tissue damage caused by LT already having reached its molecular
targets inside cells. Mortality usually follows when the host fails to repair this damage, the so called “point-of-no-
return” for current therapy. Thus, even with intensive medical care, the mortality rate of systemic anthrax is high,
reaching > 50%. Therefore, there is an urgent unmet clinical need to develop better targeted therapies to avert
anthrax -induced mortality. Our goal in this application is to discover the molecular mechanisms underlying LT-
induced lethality and to develop potential targeted therapeutics to treat patients beyond the “point-of-no-return”.
Here, we set out to determine the specific roles of disrupting each of the ERK, p38, and JNK pathways in anthrax-
induced lethality, discover the underlying molecular mechanisms, and develop the concept of reactivation
/mobilization of these pathways as a targeted therapy for anthrax-induced mortality. In Aim 1, we will determine
the role of specifically disrupting the ERK pathway in anthrax-induced lethality and explore ERK pathway
reactivation as a targeted therapy. Among the three core MAPK pathways targeted by LT, the ERK pathway is
fundamental to many biological processes, including cell proliferation and survival. Thus, we hypothesize that
disrupting the ERK pathway is the major cause of anthrax-induced lethality. We will generate and use novel
mouse models containing MEK1 and MEK2 alleles that are resistant to LT-cleavage to understand the precise
role of ERK pathway inactivation in anthrax pathogenesis. We will further test this hypothesis and explore ERK
pathway reactivation as a targeted therapy for anthrax-induced tissue damage. Importantly, our preliminary data
demonstrate that the LT-disrupted ERK pathway can be reactivated by the addition of potent mitogens, such as
epidermal growth factor. In Aim 2, we will further determine the roles of disrupting the p38 and JNK pathways in
anthrax pathogenesis and explore the feasibility of mobilizing these pathways in anthrax-targeted therapy.
Upon completion of these studies, it is our expectation that we will provide significant conceptual advances in
our understanding of the underlying molecular mechanisms of anthrax LT and offer an evidence-based
framework for developing anthrax-targeted therapies, which will complement the current therapies with
antibiotics and anti-toxin antibodies, to prevent anthrax mortality, even at advanced stages of anthrax infection.
摘要
炭疽芽孢杆菌是炭疽病的病原体,自
2001年,炭疽病袭击。炭疽杆菌通过细菌感染和毒血症的组合导致炭疽病。作为一名
炭疽致死毒素(LT)是该病的主要毒力因子,在疾病的多个阶段起着至关重要的作用。
由于炭疽病病程很快,尤其是吸入性的非特异性、流感样症状
炭疽病,患者通常在疾病已处于中晚期时寻求医疗帮助,使
炭疽病患者的临床管理是一项极具挑战性的任务。目前的治疗方法包括抗生素。
和抗毒素抗体,分别消除病原体和中和毒素。然而,没有
可用于处理已经到达其分子的LT引起的细胞/组织损伤的治疗方法
牢房内的目标。当宿主不能修复这种损伤时,死亡通常会随之而来,即所谓的“临界点”
Return“是目前的治疗方法。因此,即使在重症监护下,系统性炭疽病的死亡率也很高,
达到50%。因此,迫切需要开发更好的靶向疗法,以避免
炭疽热导致的死亡。我们在这项应用中的目标是发现LT-
诱导致命性,并开发潜在的靶向疗法,以治疗超出“不返回点”的患者。
在这里,我们开始确定在炭疽病中干扰ERK、p38和JNK通路的具体作用-
诱导致死,发现潜在的分子机制,并发展重新激活的概念
/动员这些途径作为针对炭疽病所致死亡的靶向治疗。在目标1中,我们将确定
特异性阻断ERK信号通路在炭疽病致死中的作用及ERK信号通路的探讨
重新激活作为一种靶向治疗。在LT靶向的三个核心MAPK通路中,ERK通路是
是许多生物过程的基础,包括细胞增殖和生存。因此,我们假设
破坏ERK通路是炭疽病致死的主要原因。我们将生成并使用小说
含有MEK1和MEK2等位基因的小鼠模型对LT-裂解的抗性
ERK途径失活在炭疽病发病中的作用。我们将进一步检验这一假说,并探索ERK
途径重新激活作为炭疽热诱导的组织损伤的靶向治疗。重要的是,我们的初步数据
证明LT破坏的ERK通路可以通过添加有效的有丝分裂原重新激活,例如
表皮生长因子。在目标2中,我们将进一步确定干扰p38和JNK通路在
炭疽病的发病机制,并探讨在炭疽靶向治疗中动员这些途径的可行性。
这些研究完成后,我们期望在以下方面取得重大的概念上的进展
我们对炭疽热的潜在分子机制的理解,并提供了一个循证的
开发炭疽靶向疗法的框架,这将补充目前的疗法
抗生素和抗毒素抗体,以防止炭疽死亡,即使在炭疽感染的晚期也是如此。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Shihui Liu其他文献
Shihui Liu的其他文献
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{{ truncateString('Shihui Liu', 18)}}的其他基金
Mechanisms of anthrax lethal toxin-induced mortality and the novel biological-based targeted therapies
炭疽致死毒素致死机制及新型生物靶向治疗
- 批准号:
10654406 - 财政年份:2023
- 资助金额:
$ 51.75万 - 项目类别:
Developmental therapy for selectively targeting MEK-ERK pathway in cancer cells and tumor stromal compartment
选择性靶向癌细胞和肿瘤基质室中 MEK-ERK 通路的发育疗法
- 批准号:
10092258 - 财政年份:2021
- 资助金额:
$ 51.75万 - 项目类别:
Developmental therapy for selectively targeting MEK-ERK pathway in cancer cells and tumor stromal compartment
选择性靶向癌细胞和肿瘤基质室中 MEK-ERK 通路的发育疗法
- 批准号:
10589930 - 财政年份:2021
- 资助金额:
$ 51.75万 - 项目类别:
Developmental therapy for selectively targeting MEK-ERK pathway in cancer cells and tumor stromal compartment
选择性靶向癌细胞和肿瘤基质室中 MEK-ERK 通路的发育疗法
- 批准号:
10386764 - 财政年份:2021
- 资助金额:
$ 51.75万 - 项目类别:
Defining cellular receptors for the Bacillus cereus hemolysin BL toxin (HBL) and the development of anti-HBL therapies
蜡样芽孢杆菌溶血素 BL 毒素 (HBL) 细胞受体的定义和抗 HBL 疗法的开发
- 批准号:
10550183 - 财政年份:2020
- 资助金额:
$ 51.75万 - 项目类别:
Defining cellular receptors for the Bacillus cereus hemolysin BL toxin (HBL) and the development of anti-HBL therapies
蜡样芽孢杆菌溶血素 BL 毒素 (HBL) 细胞受体的定义和抗 HBL 疗法的开发
- 批准号:
10327318 - 财政年份:2020
- 资助金额:
$ 51.75万 - 项目类别:
Defining cellular receptors for the Bacillus cereus hemolysin BL toxin (HBL) and the development of anti-HBL therapies
蜡样芽孢杆菌溶血素 BL 毒素 (HBL) 细胞受体的定义和抗 HBL 疗法的开发
- 批准号:
9973309 - 财政年份:2020
- 资助金额:
$ 51.75万 - 项目类别:
Defining cellular receptors for the Bacillus cereus hemolysin BL toxin (HBL) and the development of anti-HBL therapies
蜡样芽孢杆菌溶血素 BL 毒素 (HBL) 细胞受体的定义和抗 HBL 疗法的开发
- 批准号:
10112820 - 财政年份:2020
- 资助金额:
$ 51.75万 - 项目类别:
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