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Neuro-Immune Mechanisms in Early Life Stress-Induced Gastrointestinal Disease

生命早期压力诱发的胃肠道疾病的神经免疫机制

基本信息

批准号：
10413828
负责人：
Adam Moeser
金额：
$ 44.56万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413828
关键词：
Abdominal Pain Adult Agriculture Androgens Animals Applications Grants Automobile Driving Biogenesis Biological Biology Cell Degranulation Cellular biology Chronic Clinical Cytoplasmic Granules Development Disease Disease susceptibility Economics Elderly Engraftment Epigenetic Process Exhibits Exposure to Family suidae Female Food Hypersensitivity Functional disorder Future Gastrointestinal Diseases Gastrointestinal Physiology Genetic Transcription Goals Gonadal Steroid Hormones Histamine Human Hyperactivity Immune Immune System Diseases Immune signaling Immune system Industry Inflammatory Bowel Diseases Intestines Irritable Bowel Syndrome Knowledge Lead Leaky Gut Life Link Longevity Mediator of activation protein Morbidity - disease rate Mus Neuroimmune Neuroimmune system Neuroimmunomodulation Patients Peptide Hydrolases Perinatal Persons Phenotype Plague Play Practice Management Predisposition Prevalence Prevention Production Public Health Research Risk Risk Factors Role Serotonin Severity of illness Sex Bias Sex Differences Shapes Stress Testing Therapeutic Therapeutic Intervention Tissues Weaning abuse neglect biological sex cell motility critical period design disorder risk early life adversity early life stress experience gastrointestinal gastrointestinal system inhibitor intestinal barrier lifetime risk male mast cell mature animal mortality neonate neuroinflammation new technology new therapeutic target novel novel therapeutics porcine model postnatal development prenatal programs resilience sex sex development disorder sexual dimorphism stem cells targeted biomarker therapeutic target

项目摘要

PROJECT SUMMARY Exposure to early life adversity (ELA) during critical periods of prenatal and postnatal development is an important risk factor for the later life onset of highly prevalent gastrointestinal (GI) diseases, including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). The precise mechanisms linking ELA and GI disease susceptibility are unknown and thus management and therapeutic targets and biomarkers are lacking. Our studies using a porcine model demonstrated that ELA alters the normal course of GI development resulting in lifelong intestinal barrier dysfunction or “leaky gut', neuroimmune dysregulation and increased GI disease that recapitulates much of the pathophysiology and clinical features of human stress-related GI disorders. We recently identified two factors associated with ELA-induced GI disease susceptibility and severity in adulthood: (1) heightened and persistent intestinal mast cell hyper-activity and (2) biological sex with females at increased risk and males protected. Furthermore, we have identified novel sex-differences in the mast cell phenotype in that mast cell from female animals exhibit enhanced synthesis storage and stress-induced release of mediators such as histamine, proteases and serotonin which have known roles in GI neuroimmune disorders. Our hypothesis is that mast cells and biological sex interact to organize the development of GI barrier and neuroimmune systems, consequently determining the lifetime risk to disease following exposure to ELA. We have designed three specific aims to accomplish this objective. Aim 1 will test the hypothesis that hyper-activation of GI mast cells during early postnatal development lead to GI barrier and neuroimmune dysfunction in adulthood. Aim 2 will test the hypothesis that the heightened vulnerability of females to ELA-induced GI disease depends on androgens acting during early development. Aim 3 will test the hypothesis that ELA and perinatal androgens program mast cells, via epigenetic and transcriptional mechanisms, resulting in mast cell hyperactivity which drives GI barrier and neuroimmune dysfunction into adulthood. Together, the studies proposed in the grant application are expected to result in a major paradigm shift in the understanding the origins of ELA-induced and sex-biased GI neuroimmune diseases which could ultimately unveil new therapeutic targets to protect the GI system during vulnerable periods of stress and to therapeutically modulate adult diseases in both sexes.

项目总结