Mannose binding lectin-dependent complement activation in emphysema

肺气肿中甘露糖结合凝集素依赖性补体激活

基本信息

批准号：
10534745
负责人：
Karina Serban
金额：
$ 15.87万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-17 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534745
关键词：
Address Animals Antigen-Antibody Complex Apical Area Bacterial Infections Binding Biological Assay Biological Markers Biology Calorimetry Cause of Death Cell surface Cells Chronic Obstructive Pulmonary Disease Co-Immunoprecipitations Code Collaborations Committee Members Complement Complement Activation Data Deposition Development Disease Disease Progression Energy Transfer Ensure Environment Enzymatic Biochemistry Enzyme-Linked Immunosorbent Assay Epithelial Cells Epithelium Event Fluorescence Fluorescence Resonance Energy Transfer Health Human In Vitro Incidence Individual Infection Inflammation Injury Kidney Lectin Link Liquid substance Lung Lung diseases MASP2 gene Mannose Binding Lectin Measurement Measures Mentors Mus Myocardial Ischemia Pathogenicity Pathway interactions Peptide Hydrolases Phase Point Mutation Positioning Attribute Predisposition Protease Inhibitor Protein Isoforms Pulmonary Emphysema Pulmonary Inflammation Reperfusion Therapy Reporting Research Research Personnel Role Sampling Serine Serine Protease Serine Proteinase Inhibitors Serum Severity of illness Signal Transduction Smoke Smoker Smoking Sterility Structure of parenchyma of lung Surface Techniques Testing Tissues Titrations Training Translating Trypsin Wild Type Mouse airway epithelium alpha 1-Antitrypsin alpha 1-Antitrypsin Deficiency cell injury cigarette smoke cigarette smoke-induced cigarette smoke-induced inflammation cigarette smoke-induced lung injury cigarette smoking clinically relevant complement pathway complement system design early onset experimental study exposure to cigarette smoke fluorescence lifetime imaging follower of religion Jewish improved in vivo inhibitor lung injury mortality mouse model novel novel therapeutics pathogen protective pathway recruit response skills tissue injury translational study

项目摘要

Project summary The mechanisms by which cigarette smoke (CS) activates the complement cascade to cause lung sterile inflammation and COPD progression are not completely understood. Considering the critical role of complement in pathogen-induced inflammation, selective inhibition of the mannose-binding lectin (MBL) complement pathway may result in decreased CS-induced inflammation and emphysema-like airspace enlargement without an indiscriminate inhibition of complement's response to pathogens. In Aim 1 we propose to investigate a novel mechanism of CS-induced lung injury; focusing on whether mannose-binding lectin associated serine protease-2 (MASP-2), the central protease in the MBL pathway, is necessary to induce inflammation and emphysema during CS exposure. In Aim 2 we will investigate whether alpha-1 antitrypsin, a major serine protease inhibitor, binds and inhibits MASP-2. My proposal addresses the clinically relevant question whether selective targeting of complement cascade via MASP-2 inhibition ameliorates lung inflammation and emphysema development in relevant murine models of CS exposure. Our animal studies are complemented by measurements of MASP-2 levels and activity in samples from active smokers with and without COPD. The design and implementation of the proposed coursework and experiments will assist me in gaining expertise in complement biology, enzymology, and perfect my skills in lung stereology. I will train in new techniques, such as miscroscale thermophoresis, isothermal titration calorimetry, and fluorescence resonance energy transfer, FRET - fluorescence lifetime imaging microscopy, FLIM to study alpha-1 antitrypsin binding to MASP-2. These skills and the new research focus on the role of complement system in CS-induced sterile inflammation will allow me to become an independent investigator in a different area of research than my mentor, Dr. Petrache. My committee members and collaborators are strategically positioned to assist me in completing this proposal. National Jewish Health environment, the extraordinary expertise of the mentoring team, and the track record of fruitful collaborations between Dr. Petrache and members of the committee, will ensure a multifaceted and nurturing setting to facilitate my transition to independence. Completion of this project will provide compelling experimental evidences that MASP-2 inhibition using protease inhibitors ameliorates inflammation and lung injury in murine models of emphysema and it can be harnessed as next generation therapeutics in human COPD disease.

项目摘要香烟烟雾（CS）激活补体级联导致肺无菌的机制炎症和COPD进展尚不完全了解。考虑到关键作用补充病原体诱导的炎症，选择性抑制甘露糖结合凝集素（MBL）补体途径可能导致CS诱导的炎症和肺气肿状空域减少扩大没有歧视的补体对病原体的反应的抑制作用。在AIM 1中，我们建议研究CS诱导的肺损伤的新机制；专注于甘露糖结合凝集素是否相关的丝氨酸蛋白酶-2（MASP-2），MBL途径中的中心蛋白酶，必须诱导 CS暴露期间的炎症和肺气肿。在AIM 2中，我们将研究Alpha-1抗胰蛋白酶是否是主要的丝氨酸蛋白酶抑制剂，结合并抑制MASP-2。我的建议涉及临床上相关的疑问通过MASP-2抑制选择性靶向补体级联是否可以改善肺 CS暴露的相关鼠模型中的炎症和肺气肿发育。我们的动物研究是通过测量MASP-2水平的测量和活性吸烟者的样品的测量和活性没有COPD。拟议的课程和实验的设计和实施将有助于我获得补充生物学，酶学和完美我在肺立体学方面的技能方面的专业知识。我将训练新的技术，例如混杂效果，等温滴定量热法和荧光共振能量转移，FRET-荧光寿命成像显微镜，FLIM以研究α -1抗胰蛋白酶结合 MASP-2。这些技能和新的研究集中于补体系统在CS引起的无菌中的作用炎症将使我成为与我的研究领域不同的独立研究者导师，彼得拉奇博士。我的委员会成员和合作者在战略上可以协助我完成了这一建议。国家犹太人健康环境，非凡的专业知识指导团队，以及彼得拉奇博士和成员之间富有成果合作的记录委员会将确保一个多方面和培养的环境，以促进我向独立过渡。该项目的完成将提供令人信服的实验证据，使MASP-2抑制使用蛋白酶抑制剂可以改善肺气肿的鼠模型中的炎症和肺损伤，并且可以是作为人类COPD疾病的下一代治疗方法。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Alpha-1 antitrypsin inhibits fractalkine-mediated monocyte-lung endothelial cell interactions.

Alpha-1 抗胰蛋白酶抑制 fractalkine 介导的单核细胞-肺内皮细胞相互作用。

DOI：
10.1152/ajplung.00023.2023
发表时间：
2023
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
Mikosz,Andrew;Ni,Kevin;Gally,Fabienne;Pratte,KatherineA;Winfree,Seth;Lin,Qiong;Echelman,Isabelle;Wetmore,Brianna;Cao,Danting;Justice,MatthewJ;Sandhaus,RobertA;Maier,Lisa;Strange,Charlie;Bowler,RussellP;Petrache,Irina;Serb
通讯作者：
Serb

Lectin Complement Pathway in Emphysema.

肺气肿中的凝集素补体途径。

DOI：
10.1164/rccm.201807-1380le
发表时间：
2019
期刊：
American journal of respiratory and critical care medicine
影响因子：
24.7
作者：
Serban,KarinaA;Mikosz,Andrew;Strange,Charlie;Janciauskiene,SabinaM;Stolk,Jan;Jonigk,Danny;Sandhaus,RobertA;Petrache,Irina
通讯作者：
Petrache,Irina

The multifaceted protease-anti-protease imbalance in COVID-19.

DOI：
10.1016/j.ebiom.2022.103973
发表时间：
2022-04
期刊：
EBioMedicine
影响因子：
11.1
作者：
Goel K;Serban KA
通讯作者：
Serban KA

A 56-Year-Old Man With Emphysema, Rash, and Arthralgia.

一名 56 岁男性，患有肺气肿、皮疹和关节痛。

DOI：
10.1016/j.chest.2021.06.045
发表时间：
2021
期刊：
Chest
影响因子：
9.6
作者：
Goel,Khushboo;Maleki-Fischbach,Mehrnaz;George,MPatricia;Kim,Darlene;Richards,John;Wise,RobertA;Serban,KarinaA
通讯作者：
Serban,KarinaA

Can Metformin Downshift the Gears of Aging to Slow Emphysema Progression?