PGC-1 alpha in Lung Immune Response

PGC-1 α 在肺免疫反应中的作用

• 批准号: 10368226
• 负责人: Ruxana T Sadikot
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368226
• 关键词: Agonist; Attenuated; Bacteria; Bioenergetics; Biogenesis; Cell physiology; Clinical Trials; Data; Diabetes Mellitus; Drug resistance; Enzymes; Epithelial Attachment; Epithelial Cells; Epithelium; FDA approved; Functional disorder; Funding; Genes; Genetic; Glycolysis; Goals; Health; Hospitalization; Host Defense; Host resistance; Human; Hydrolysis; Immune; Immune response; Immunocompromised Host; Immunologic Stimulation; Impairment; In Vitro; Infection; Inflammasome; Inflammatory Response; Innate Immune Response; Ligands; Lung; Lung immune response; Lung infections; Metformin; Microbial Biofilms; Mitochondria; Molecular; Multi-Drug Resistance; Mus; PPAR gamma; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pioglitazone; Post-Transcriptional Regulation; Production; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Reactive Oxygen Species; Resistance; Role; Signal Transduction; Testing; Transcriptional Regulation; Translating; Type III Secretion System Pathway; Veterans; Virulence; Virulence Factors; Virulent; Work; airway epithelium; attenuation; bronchial epithelium; clinical translation; combat; factor A; gain of function; immune function; improved; improved outcome; in vivo; insight; lipid mediator; loss of function; migration; military veteran; mortality; mouse model; mtTF1 transcription factor; mutant; novel; novel therapeutic intervention; novel therapeutics; overexpression; pathogen; pharmacologic; preclinical study; prevent; resistant strain; response; shift work; small molecule; tool; transcription factor

Pseudomonas aeruginosa is a major health challenge that causes recalcitrant multi-drug resistant infections, especially in immunocompromised and hospitalized patients. Multi- and pan-drug resistant strains of P. aeruginosa are increasing threats that contribute to high mortality in these patients (1-3). Hence, there is an urgent need to develop new strategies to combat P. aeruginosa and other resistant pathogens. The pathogenic profile of P. aeruginosa is related to its ability to secrete a variety of virulence factors. Novel therapeutic strategies that strengthen the ability of the host would enhance immune defenses and improve outcomes. Over the previous funding cycle, we elucidated the mechanisms by which lipid mediators regulate the lung’s innate immune responses to P. aeruginosa virulence factors (5-8). We discovered that 15d-PGJ2, stimulates host responses to P. aeruginosa through peroxisome proliferator-activated receptor gamma (PPAR), a ligand- activated transcription factor (9-11). Further, we showed that PPAR agonists inhibit P. aeruginosa biofilm formation and enhance bacterial clearance from the lungs. Studies to determine the mechanisms by with PPAR modulates host response in epithelial cells revealed that P. aeruginosa : 1) inhibit paraoxanase-2, a key mitochondrial enzyme that hydrolyses C12-HSL (12, 13), and 2) inhibit PPAR coactivator 1-alpha (PGC- 1α) and mitochondrial transcription factor A (TFAM), disrupting mitochondrial biogenesis and bioenergetics (14,15). These mitochondrial derangements impaired epithelial ATP production, increased reactive oxygen species (ROS), and enhanced glycolysis to disrupt epithelial barrier integrity and immune function. Most importantly, our new data show that PGC-1α overexpression or activation rescues mitochondrial bioenergetics and epithelial junctional integrity preventing bacterial transmigration in vitro and enhancing clearance of bacteria in lungs of mice infected with P. aeruginosa in vivo. Therefore, we hypothesize that P. aeruginosa evades host defenses by disrupting mitochondrial biogenesis, epithelial barrier integrity, and immune function. Strategies to restore PGC-1α provide a novel therapeutic approach to stimulate mitochondrial biogenesis and enhance immune function in P. aeruginosa lung infections. To test this hypothesis, we propose three specific aims: 1) Investigate the molecular mechanisms by which P. aeruginosa attenuates PGC-1α in host lung epithelial cells.2) Elucidate how attenuation of PGC-1α compromises host epithelial barrier and immune function in response to P. aeruginosa. 3) Define the impact of rescuing PGC-1α activation and mitochondrial biogenesis in P. aeruginosa pneumonia in vivo. The PI’s investigative team provides needed and complementary expertise to advance this paradigm-shifting work focused on enhancing host resistance to invasive pathogens. Successful completion of these integrated studies will provide new insights into the molecular pathogenesis of P. aeruginosa-induced airway epithelial cell dysfunction (Aim 1), define novel pathways perturbing critical host cell functions (Aim 2), and explore new therapeutic paradigms for restoring cell functions involved in host defense (Aim 3). The overarching goal of this proposal is to define novel molecular approaches to rescue host mitochondrial function and immune responses to pathogens such as P. aeruginosa. The impact of these studies is further enhanced by their potential relevance to other pathogens and by the exploration of existing pharmacological tools permitting rapid clinical translation and benefit to veterans infected with virulent pathogens.

铜绿假单胞菌是引起顽固性多重耐药的主要健康挑战

项目成果

Pulmonary artery dissection and rupture in a patient with idiopathic pulmonary artery hypertension.

特发性肺动脉高压患者的肺动脉夹层和破裂。

• DOI: 10.1164/rccm.201304-0693im
• 发表时间: 2014
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Patel,Vipul;Mehta,HirenJ;Sadikot,RuxanaT
• 通讯作者: Sadikot,RuxanaT

Celecoxib improves host defense through prostaglandin inhibition during Histoplasma capsulatum infection.

塞来昔布在荚膜组织胞浆菌感染期间通过抑制前列腺素来改善宿主防御。

• DOI: 10.1155/2013/950981
• 发表时间: 2013
• 期刊: Mediators of inflammation
• 影响因子: 4.6
• 作者: Pereira,PriscillaAparecidaTartari;Trindade,BrunoCaetano;Secatto,Adriana;Nicolete,Roberto;Peres-Buzalaf,Camila;Ramos,SimoneGusmão;Sadikot,Ruxana;Bitencourt,ClaudiadaSilva;Faccioli,LúciaHelena
• 通讯作者: Faccioli,LúciaHelena

TREM-1 is induced in tumor associated macrophages by cyclo-oxygenase pathway in human non-small cell lung cancer.

• DOI: 10.1371/journal.pone.0094241
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Yuan Z;Mehta HJ;Mohammed K;Nasreen N;Roman R;Brantly M;Sadikot RT
• 通讯作者: Sadikot RT

Bacterial Infections Associated with Immunosuppressive Agents Commonly Used in Patients with Interstitial Lung Diseases.

• DOI: 10.3390/pathogens12030464
• 发表时间: 2023-03-15
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Chaaban S;Sadikot RT
• 通讯作者: Sadikot RT

Induction of cyclooxygenase-2 signaling by Stomatococcus mucilaginosus highlights the pathogenic potential of an oral commensal.

粘液口球菌对环氧合酶 2 信号的诱导凸显了口腔共生菌的致病潜力。

• DOI: 10.4049/jimmunol.1300883
• 发表时间: 2013
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Yuan,Zhihong;Panchal,Dipti;Syed,MansoorAli;Mehta,Hiren;Joo,Myungsoo;Hadid,Walid;Sadikot,RuxanaT
• 通讯作者: Sadikot,RuxanaT