Statins as Inhibitors of Bacterial Host Cell Invasion

他汀类药物作为细菌宿主细胞侵袭的抑制剂

基本信息

批准号：
7454721
负责人：
SUSAN A MCDOWELL
金额：
$ 21.68万
依托单位：
BALL STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7454721
关键词：
1-Phosphatidylinositol 4-Kinase Address Antibiotics Bacteria Binding Biological Preservation CDC42 gene Cardiac Cardiovascular Physiology Cell membrane Cells Cessation of life Cholesterol Chronic Clinical Communicable Diseases Coupled Coupling Critical Illness Cytosol Data Development Dose Effectiveness Endocarditis Endothelial Cells Exposure to Genetic Gentamicins Goals In Vitro Infection Inflammatory Response Ingestion Invasive Investigation Lead Lipids Mediating Membrane Modeling Molecular Monomeric GTP-Binding Proteins Mus Numbers Pathogenesis Pathway interactions Patients Phagocytes Pharmaceutical Preparations Phosphatidylinositols Phosphotransferases Protein Isoforms Proteins Public Health Recurrence Research Risk Safety Saline Sepsis Signal Pathway Signal Transduction Simvastatin Staphylococcus aureus Students Systemic infection Testing Therapeutic Tissues Treatment Protocols Work attenuation bactericide cdc42 GTP-Binding Protein cholesterol biosynthesis extracellular hemodynamics immunoregulation improved in vivo in vivo Model infectious disease treatment inhibitor/antagonist isoprenoid kinase inhibitor mimetics novel outcome forecast pathogen prenyl prenylation prevent protective effect research study response small molecule uptake

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this research is to understand the molecular mechanisms of bacterial host cell invasion both in vitro and in vivo. Clinical evidence indicates improved prognosis for patients on a statin regimen prior to bacterial sepsis. While some of these beneficial effects have been attributed to improved hemodynamics or immunomodulation, we have recently found that therapeutic concentrations of simvastatin in vitro inhibits host invasion by Staphylococcus aureus, the most common etiologic agent in sepsis. Inhibition appears to be due primarily to the depletion of isoprenoid intermediates by simvastatin within the cholesterol biosynthesis pathway rather than to the depletion of cholesterol itself. Simvastatin also led to the cytosolic accumulation of CDC42 coupled to the phosphoinositide 3-kinase (PI3K) regulatory subunit p85. The proposed hypothesis is that simvastatin inhibits host invasion in part through sequestration of PI3K isoforms within the cytosol. Proposed studies will use genetic approaches to sequester PI3K within the cytosol and assess whether host invasion is decreased. In vivo models of infection will be used to assess whether the inhibition of host invasion increases antibiotic efficacy and prevents chronic, persistent infection, or conversely, whether simvastatin inhibition of uptake by non-professional phagocytes impairs innate clearance. Together, the proposed experiments will address a potentially novel mechanism in the action of statins that could lead to more directed therapeutics to circumvent issues in statin use as an adjunct therapy for infectious disease. The cholesterol-lowering drugs known as statins have a number of non-cholesterol lowering benefits, including a decreased risk of death due to systemic infection. This proposed work will engage undergraduate and master's level students in the investigation of the protective effect of statins, pursuing the question of whether statins block infection, with an overall goal of developing adjunctive therapies for the treatment of infectious disease. PUBLIC HEALTH RELEVANCE: The cholesterol-lowering drugs known as statins have a number of non-cholesterol lowering benefits, including a decreased risk of death due to systemic infection. This proposed work will engage undergraduate and master's level students in the investigation of the protective effect of statins, pursuing the question of whether statins block infection, with an overall goal of developing adjunctive therapies for the treatment of infectious disease.

描述（由申请人提供）：这项研究的长期目标是了解细菌宿主细胞在体外和体内的分子机制。临床证据表明，在细菌败血症之前，汀类药物方案患者的预后有所改善。尽管其中一些有益作用归因于改善的血液动力学或免疫调节，但我们最近发现，辛伐他汀在体外的治疗浓度抑制了金黄色葡萄球菌的宿主侵袭，金黄色葡萄球菌是脓毒症中最常见的病因学剂。抑制作用似乎主要是由于胆固醇生物合成途径中辛伐他汀的类异丙定中间体的耗竭，而不是胆固醇本身的耗竭。辛伐他汀还导致Cdc42与磷酸肌醇3-激酶（PI3K）调节亚基P85的胞质积累。提出的假设是，辛伐他汀在细胞质内的PI3K同工型部分抑制宿主侵袭。拟议的研究将使用遗传方法隔离细胞质内的PI3K，并评估宿主侵袭是否降低。体内感染模型将用于评估宿主侵袭的抑制是否会提高抗生素功效并防止慢性，持续感染，还是相反，是否会抑制非专业吞噬细胞对摄入的抑制，是否会损害先天性的清除。共同提出的实验将解决他汀类药物作用中一种潜在的新型机制，该机制可能导致更有方向性的治疗剂规避他汀类药物作为传染病的辅助疗法的问题。降低胆固醇的药物称为他汀类药物有许多非胆固醇降低的益处，包括由于全身感染而导致死亡的风险降低。这项拟议的工作将吸引本科生和硕士水平的学生参与他汀类药物的保护作用的调查，并提出汀类药物阻滞感染的问题，即是否开发辅助疗法以治疗传染病。公共卫生相关性：降低胆固醇的药物（称为他汀类药物）具有许多非胆固醇降低的益处，包括由于全身感染而导致死亡的风险降低。这项拟议的工作将吸引本科生和硕士水平的学生参与他汀类药物的保护作用的调查，并提出汀类药物阻滞感染的问题，即是否开发辅助疗法以治疗传染病。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Short term statin treatment improves survival and differentially regulates macrophage-mediated responses to Staphylococcus aureus.

短期他汀类药物治疗可提高生存率并差异调节巨噬细胞介导的金黄色葡萄球菌反应。

DOI：
10.2174/138920113805219395
发表时间：
2013
期刊：
Current pharmaceutical biotechnology
影响因子：
2.8
作者：
Burns,ErinM;Smelser,LisaK;Then,JennyE;Stankiewicz,TraciE;Kushdilian,Michael;McDowell,SusanA;Bruns,HeatherA
通讯作者：
Bruns,HeatherA

GTPase activating protein function of p85 facilitates uptake and recycling of the beta1 integrin.

p85 的 GTP 酶激活蛋白功能促进 β1 整合素的摄取和再循环。

DOI：
10.1016/j.bbrc.2009.11.077
发表时间：
2010
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Stankiewicz,TraciE;Haaning,KelseyL;Owens,JanelleM;Jordan,AlysS;Gammon,Kelly;Bruns,HeatherA;McDowell,SusanA
通讯作者：
McDowell,SusanA