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Role of intestinal microbiome and gut permeability in the development of Kawasaki Disease vasculitis

肠道微生物组和肠道通透性在川崎病血管炎发生中的作用

基本信息

批准号：
10310487
负责人：
Magali Noval Rivas
金额：
$ 43.75万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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：
2018-01-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310487
关键词：
5 year old Acute Affect Aneurysm Antibiotics Antifungal Agents Aortic Aneurysm Area B-Lymphocytes BLR1 gene Bacteria Blood Circulation Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Compartmentation Cell Wall Cells Cessation of life Child Childhood Clinical Data Communities Complex Coronary Coronary Aneurysm Coronary artery Data Deposition Development Disease Distant Etiology Event FOXP3 gene Fever Gastrointestinal tract structure Germ-Free Goals Heart Diseases Human Illness Days Immune Immune System Diseases Immune response Immunoglobulin A Immunoglobulin G Immunologics Interleukin-1 Intervention Intestinal permeability Intestines Intravenous Intravenous Immunoglobulins Lactobacillus casei Lead Leaky Gut Lesion Link Measures Modeling Molecular Mucocutaneous Lymph Node Syndrome Mucosal Immune Responses Mucosal Immune System Mucous Membrane Mus Myocardial Infarction Myocardial Ischemia Organism Pathogenesis Pathogenicity Pathology Patients Physiology Pilot Projects Plasma Cells Play Prevention Prevention approach Preventive Regulatory T-Lymphocyte Research Resistance Risk Role Secretory Immunoglobulin A Serum Shapes Site Testing Therapeutic Tissues Vasculitis abdominal aorta autoimmune vasculitis base beta-Glucans commensal microbes coronary arteritis dectin 1 disease diagnosis dysbiosis effective therapy fungus gastrointestinal gastrointestinal symptom gut colonization gut microbiome gut microbiota high risk immunopathology improved microbial community microbiome alteration microbiota microorganism mouse model mycobiome new therapeutic target novel strategies novel therapeutic intervention novel therapeutics prevent programmed cell death protein 1 receptor response translational potential zonulin

项目摘要

PROJECT ABSTRACT Kawasaki disease (KD) is an acute febrile illness/systemic vasculitis of unknown etiology that predominantly afflicts young children, causes coronary artery abnormalities and aneurysms (CAA), and could potentially result in long-term cardiovascular sequelae and even death. KD vasculitis is the leading cause of acquired heart disease among children in the US. CAA develop in 25% of untreated children with KD, leading to ischemic heart disease and myocardial infarction. While Intravenous immunoglobulin (IVIG) treatment lowers the risk of CAA to 5%, up to 25% of KD patients are IVIG-resistant and have a greater risk for CAA. Therefore, discovery of more effective treatments to prevent the cardiovascular complications of KD vasculitis is a high priority in pediatric and cardiovascular research. The intestinal microbiome is an integral part of our physiology and intestinal dysbiosis influences the development of a number of immunological and non-immunological diseases, including cardiovascular diseases. In preliminary studies, we discovered striking new evidence that intestinal microbiota, gut permeability, and dysregulated mucosal immune responses play a key role in the development of coronary arteritis and aneurysm formation in KD using a well-established KD vasculitis mouse model. Based on our preliminary data, we hypothesize that intestinal dysbiosis and increased gut permeability concomitantly occur during KD and play a crucial role in modulating immune responses significantly contributing to the cardiovascular lesions associated with KD. These events will result in commensal microbiota translocation and/or bacterial/fungal PAMPs as well as increased gut permeability of metabolites, and secretory IgA into blood circulation and may play an important role in modulating and fine-tuning systemic and local immune responses helping drive the immunopathology and fuel the development of KD lesions. Deciphering the mechanisms by which the intestinal commensal micro and mycobiome and increased gut permeability affect the development of cardiovascular lesions of KD could provide a novel therapeutic target for intervention. To test this hypothesis, we propose to determine how compositional alterations of the intestinal commensals influence murine KD vasculitis pathology (Aim 1). We will investigate the role of increased intestinal permeability and determine if its prevention has therapeutic value during murine KD vasculitis. (Aim 2). We will characterize the role of secretory IgA leaking from the gut in promoting the development of cardiovascular lesions in KD vasculitis model (Aim 3). Clinical data suggest that children with KD frequently have a leaky gut and more than 80% receive microbiome altering antibiotics in the week prior to KD diagnosis. Therefore, this proposal has a very high translational potential given that specific manipulation of the commensal microbiota is a research area with high therapeutic promises. Understanding the role and the molecular mechanism by which gut microbiome and gut permeability contribute to the cardiovascular complications of KD may lead novel therapeutic and preventive approaches.

项目摘要

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Platelets exacerbate cardiovascular inflammation in a murine model of Kawasaki disease vasculitis.

DOI：
10.1172/jci.insight.169855
发表时间：
2023-07-24
期刊：
JCI INSIGHT
影响因子：
8
作者：
Kocaturk, Begum;Lee, Youngho;Nosaka, Nobuyuki;Abe, Masanori;Martinon, Daisy;Lane, Malcolm E.;Moreira, Debbie;Chen, Shuang;Fishbein, Michael C.;Porritt, Rebecca A.;Franklin, Bernardo S.;Rivas, Magali Noval;Arditi, Moshe
通讯作者：
Arditi, Moshe

NLRP3 Inflammasome Mediates Immune-Stromal Interactions in Vasculitis.

DOI：
10.1161/circresaha.121.319153
发表时间：
2021-10-15
期刊：
Circulation research
影响因子：
20.1
作者：
Porritt RA;Zemmour D;Abe M;Lee Y;Narayanan M;Carvalho TT;Gomez AC;Martinon D;Santiskulvong C;Fishbein MC;Chen S;Crother TR;Shimada K;Arditi M;Noval Rivas M
通讯作者：
Noval Rivas M

Notch1 signaling impairs regulatory T cells during multisystem inflammatory syndrome in children.