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Uncovering pathogenic anti-bacterial defense mechanisms to identify novel targets for prevention of T1D

揭示致病性抗菌防御机制以确定预防 T1D 的新靶点

基本信息

批准号：
10207399
负责人：
Nora E Sarvetnick
金额：
$ 57.94万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207399
关键词：
Adolescent Animal Model Animals Anti-Bacterial Agents Antibacterial Response Antigens Area Autoimmune Diseases Autoimmunity B-Lymphocytes Bacteria Cells Clinical Data Defense Mechanisms Development Diabetes Mellitus Diffuse Disease Duodenum Experimental Models Exposure to Extravasation Goals Human Hyperglycemia Immune Immune system Immunity Immunoglobulin A Inflammation Inflammation Mediators Insulin-Dependent Diabetes Mellitus Interleukin-17 Intestines Islets of Langerhans Leaky Gut Link Mucosal Immune Responses Mus Neutrophil Infiltration Onset of illness Pancreas Pathogenesis Pathogenicity Pathologic Pathway interactions Preclinical Testing Prevention Prevention strategy Research Role Secretory Immunoglobulin A T-Lymphocyte Testing Therapeutic Intervention base chemokine cooperative study design diabetes control disorder prevention dysbiosis experimental study immune activation in vivo insulin dependent diabetes mellitus onset insulitis interest islet microbiome mouse model novel novel therapeutic intervention prevent preventive intervention response therapeutic evaluation transcriptome

项目摘要

Abstract While contemporary research has shown Type 1 diabetes (T1D) is associated with intestinal dysbacteriosis and leakage, it is not known whether these factors cause the disease. Establishing a causative link between the onset and progression of T1D and dysbacteriosis is critical for developing effective prevention strategies. The overarching hypothesis of this application is that T1D is preceded by pancreatic bacterial exposure, which promotes an anti- bacterial response, pancreatic inflammation, insulitis, and autoimmunity. This hypothesis was formulated based on our preliminary data demonstrating: 1) heightened anti-bacterial responses in juvenile T1D; 2) pathologic responses by islets to bacteria overrepresented in the T1D microbiome; 3) pancreatic inflammation and insulitis in a mouse model of experimental leakage of bacteria into the pancreas; and 4) blockade of the anti-bacterial response protects islets from insulitis. In aim 1 we will determine whether human T1D development is preceded by a cellular and humoral anti-bacterial response and establish an association with the duodenal microbiome. We will test whether bacteria-responsive MAIT cells are activated before clinical disease develops and determine if they are differentially activated by overrepresented bacteria. Next, we will discover whether the increased anti-bacterial IgA response in T1D is directed at overrepresented bacteria. We will profile the duodenal microbiome and determine if it is associated with these defense mechanisms. In aim 2 we will ascertain whether pancreatic exposure to bacteria leads to immune activation, insulitis, and hyperglycemia. We will determine whether pancreatic islets show distinct responses to specific T1D-associated bacteria including R. gnavus, B. Dorei, and S. infantarius. Lastly, we will interrogate the mediators of inflammation and insulitis following pancreatic exposure to overrepresented bacterial species and test strategies to block the response. To accomplish this task, we have established a novel mouse animal of intestinal dysbiosis and leakage to test therapeutic interventions. The proposed experiments will identify pathogenic mechanisms that link intestinal dysbiosis and leakage to T1D uncovering new targets for prevention. These targets will undergo preclinical testing in this application. This submission is responsive to the U01 Cooperative Study Group for Autoimmune Disease Prevention (CSGADP) RFA. Broad area of interest: Pathways, mechanisms, and means best suited to practical preventive interventions. Specific research topic: Identification and elucidation of cellular and immune pathways that may provide targets for preventive interventions.

摘要