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.

抽象的 氯是一种活性气体，鉴于其大量生产和使用，它是一种持续的化学威胁 工业应用中的故意和意外释放。目前的行政补充 母申请旨在开发下一代疗法，可以显着减少 这种化学威胁释放后的死亡率和发病率。我们课题组发表的研究成果 来自我们母公司的资助共同为 PM2.5 暴露导致系统性损害这一概念铺平了道路 通过 TLR4 和氧化应激途径抑制炎症（包括神经元炎症）。最近我们有 证明 Nrf2-Keap2 系统可以代表屏障功能可能发挥作用的关键途径 维持。 Nrf2 的激活可能代表消除屏障功能障碍和 减轻氯损伤。在此补充应用程序中，我们将测试 2 个目标，除了提供机械 对氯暴露引起的心肺损伤的深入了解还将测试 2 种策略：TLR4 抑制和 Nrf2 激活缓解氯暴露引起的全身炎症。在目标 1 中，我们将检查 不同剂量的氯暴露对 TLR4 激活剂（例如氧化磷脂）生成的影响 肺表面活性剂液体及其对野生型、TLR4-/- 和 Keap1-/-小鼠。我们将研究 TLR4 抑制剂的鼻内和全身递送对保护 防止氯损伤。在目标 2 中，我们将测试血脑屏障对氯的渗透性是一个概念。 全身毒性的重要组成部分，将测试几种新型小分子 Nrf2 激活剂的影响 减少中枢神经系统和肺部炎症。为了实现这些目标并扩展研究结果 原始研究（基于我们的初步研究）我们要求提供特定的补充，以便我们能够测试 这些概念。我们相信，这个补充奖项高度响应了特殊要求 NIH 化学威胁对策 (CounterACT) 计划的补充。

项目成果

Statistical strategies for constructing health risk models with multiple pollutants and their interactions: possible choices and comparisons.

构建多种污染物及其相互作用的健康风险模型的统计策略：可能的选择和比较。

• 发表时间: 2013-10-04
• 作者: Sun, Zhichao;Tao, Yebin;Li, Shi;Ferguson, Kelly K;Meeker, John D;Park, Sung Kyun;Batterman, Stuart A;Mukherjee, Bhramar
• 通讯作者: Mukherjee, Bhramar

Exploration of the composition and sources of urban fine particulate matter associated with same-day cardiovascular health effects in Dearborn, Michigan.

探索密歇根州迪尔伯恩市城市细颗粒物的成分和来源，与当日心血管健康影响相关。

• 发表时间: 2015
• 作者: Morishita, Masako;Bard, Robert L;Kaciroti, Niko;Fitzner, Craig A;Dvonch, Timothy;Harkema, Jack R;Rajagopalan, Sanjay;Brook, Robert D
• 通讯作者: Brook, Robert D

CD36-dependent 7-ketocholesterol accumulation in macrophages mediates progression of atherosclerosis in response to chronic air pollution exposure.

巨噬细胞中 CD36 依赖性 7-酮胆固醇积累介导慢性空气污染暴露引起的动脉粥样硬化进展。

• 发表时间: 2014-10-10
• 影响因子: 20.1
• 作者: Rao, Xiaoquan;Zhong, Jixin;Maiseyeu, Andrei;Gopalakrishnan, Bhavani;Villamena, Frederick A;Chen, Lung;Harkema, Jack R;Sun, Qinghua;Rajagopalan, Sanjay
• 通讯作者: Rajagopalan, Sanjay

Exposure to Air Pollution Disrupts Circadian Rhythm through Alterations in Chromatin Dynamics.

暴露于空气污染会通过改变染色质动力学来扰乱昼夜节律。

• 发表时间: 2020-11-20
• 影响因子: 5.8
• 作者: Palanivel, Rengasamy;Vinayachandran, Vinesh;Biswal, Shyam;Deiuliis, Jeffrey A;Padmanabhan, Roshan;Park, Bongsoo;Gangwar, Roopesh Singh;Durieux, Jared C;Ebreo Cara, Elaine Ann;Das, Lopa;Bevan, Graham;Fayad, Zahi A;Tawakol, Ahmed;Jain, Mukesh K
• 通讯作者: Jain, Mukesh K

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

社区层面的社会剥夺和 2 型糖尿病患者复发性心力衰竭住院的风险。

• 发表时间: 2023-10
• 作者: Deo, Salil V;Al;Motairek, Issam;Elgudin, Yakov E;Gorodeski, Eiran;Nasir, Khurram;Rajagopalan, Sanjay;Petrie, Mark C;Sattar, Naveed
• 通讯作者: Sattar, Naveed