COUNTERACT Supplement--ASPIRE: Air Pollution: Strategies for Personalized Intervention to Reduce Exposure

COUNTERACT 补充--ASPIRE：空气污染：减少接触的个性化干预策略

• 批准号: 10218398
• 负责人: Robert Daniel Brook
• 金额: $ 12.5万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-04 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218398
• 关键词: Administrative Supplement; Air Pollution; Applications Grants; Attenuated; Award; Cardiopulmonary; Chlorine; Development; Dose; Event; Functional disorder; Funding; Gases; Generations; Grant; Heart; Industrialization; Inflammation; Injury; Liquid substance; Lung; Lung Inflammation; Modality; Molecular; Morbidity - disease rate; Mus; Neurons; Oxidative Stress Pathway; Oxides; Parents; Pathway interactions; Phospholipids; Publishing; Pulmonary Surfactants; System; TLR4 gene; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; base; blood-brain barrier permeabilization; chemical release; chemical threat; experimental study; inhibitor/antagonist; insight; mortality; novel; novel therapeutics; parent grant; personalized intervention; personalized strategies; prevent; programs; response; systemic toxicity

ABSTRACT Chlorine is a reactive gas that is a continuing chemical threat given the large amounts produced and used for industrial application from both intentional and accidental release. The current administrative supplement to the parent application is directed towards development of next generation therapeutics that can significantly reduce mortality and morbidity in the event of release of this chemical threat. The studies published by our group in from our parent grant have collectively paved the way for the concept that PM2.5 exposure results in systemic inflammation (including neuronal inflammation) through TLR4 and oxidative stress pathways. Recently we have demonstrated that the Nrf2-Keap2 system could represent a key pathway through which barrier function may be maintained. Activation of Nrf2 may represent a therapeutic modality to abrogate barrier dysfunction and attenuate chlorine injury. In this supplemental application we will test 2 aims that besides providing mechanistic insights into cardiopulmonary injury with chlorine exposure will also test 2 strategies, TLR4 inhibition and Nrf2 activation in mitigating systemic inflammation in response to chlorine exposure. In Aim 1 we will examine the effect of different doses of chlorine exposure on generation of TLR4 activators such as oxidized phospholipids in the lung surfactant fluid and the impact of these on lung and systemic inflammation in wildtype, TLR4-/- and Keap1-/-mice. We will investigate the impact of intranasal and systemic delivery of TLR4 inhibitors in protecting against chlorine injury. In Aim 2 we will test the concept that blood brain barrier permeability with chlorine is an important component of systemic toxicity and will test the impact of several novel small molecular Nrf2 activators in reducing CNS and lung inflammation. To achieve these objectives and in order to extend the findings from the original study (based on our preliminary studies) we request a specific supplement that will enable us to test these concepts. We believe that this supplemental award is highly responsive to the special request for supplements to the NIH Countermeasures Against Chemical Threats (CounterACT) program.

摘要 氯是一种活性气体，它是一种持续的化学威胁，因为大量生产和使用 工业应用，包括有意释放和意外释放。现行的行政副刊 家长申请的方向是开发下一代疗法，可以显著减少 在这种化学威胁释放的情况下的死亡率和发病率。我们小组在 我们的母公司共同为PM2.5暴露导致系统性 炎症(包括神经元性炎症)通过TLR4和氧化应激途径。最近我们有 证明了Nrf2-Keap2系统可能代表了屏障功能可能通过的关键途径 维护好了。NRF2的激活可能是消除屏障功能障碍的一种治疗方式 减轻氯气伤害。在这个补充应用程序中，我们将测试两个目标，除了提供机械性 对氯暴露所致心肺损伤的洞察也将测试两种策略，TLR4抑制和Nrf2 激活以减轻氯气暴露所致的全身炎症。在目标1中，我们将研究 不同剂量氯暴露对小鼠体内氧化磷脂等TLR4激活剂生成的影响 野生型TLR4-/-和TLR4-/-的肺表面活性物液及其对肺和全身炎症的影响 Keap1-/-小鼠。我们将研究TLR4抑制剂鼻腔和全身给药对保护 防止氯气伤害。在目标2中，我们将测试血脑屏障对氯的通透性是一种 全身毒性的重要组成部分，并将测试几种新型小分子Nrf2激活剂的影响 在减少中枢神经系统和肺部炎症方面。为了实现这些目标，并为了扩大来自 原始研究(基于我们的初步研究)我们要求提供特定的补充，使我们能够进行测试 这些概念。我们认为，这项补充裁决是对 美国国立卫生研究院应对化学威胁(中)计划的补充文件。

项目成果

Epidemiological and experimental links between air pollution and type 2 diabetes.

• DOI: 10.1177/0192623312464531
• 发表时间: 2013-02
• 期刊: Toxicologic pathology
• 影响因子: 1.5
• 作者: Liu C;Ying Z;Harkema J;Sun Q;Rajagopalan S
• 通讯作者: Rajagopalan S

Reduction of environmental pollutants for prevention of cardiovascular disease: it's time to act.

• DOI: 10.1093/eurheartj/ehaa745
• 发表时间: 2020-11-01
• 期刊: European heart journal
• 影响因子: 39.3
• 作者: Münzel T;Miller MR;Sørensen M;Lelieveld J;Daiber A;Rajagopalan S
• 通讯作者: Rajagopalan S

Ambient Air Pollution and Atherosclerosis: Recent Updates.

• DOI: 10.1007/s11883-021-00958-9
• 发表时间: 2021-08-21
• 期刊: Current atherosclerosis reports
• 影响因子: 5.8
• 作者: Bevan GH;Al-Kindi SG;Brook R;Rajagopalan S
• 通讯作者: Rajagopalan S

Neighbourhood-level social deprivation and the risk of recurrent heart failure hospitalizations in type 2 diabetes.

• DOI: 10.1111/dom.15174
• 发表时间: 2023-10
• 期刊: DIABETES OBESITY & METABOLISM
• 影响因子: 5.8
• 作者: Deo, Salil V. V.;Al-Kindi, Sadeer;Motairek, Issam;Elgudin, Yakov E. E.;Gorodeski, Eiran;Nasir, Khurram;Rajagopalan, Sanjay;Petrie, Mark C. C.;Sattar, Naveed
• 通讯作者: Sattar, Naveed

Air pollution and type 2 diabetes: mechanistic insights.

• DOI: 10.2337/db12-0190
• 发表时间: 2012-12
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Rajagopalan S;Brook RD
• 通讯作者: Brook RD