Fetal Cell Senescence Signals Initiation of Parturition

胎儿细胞衰老标志着分娩的开始

• 批准号: 9454525
• 负责人: RAMKUMAR MENON
• 金额: $ 13.98万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-20 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9454525
• 关键词: Acetylation; Address; Affect; Aging; Amniotic Fluid; Apical; Area; B-Lymphocytes; Biochemistry; Biological; Biological Markers; Birth; Cell Aging; Cell Nucleus; Cell membrane; Cells; Chorion; Cytosol; Data; Diagnosis; Diffusion; Electron Microscopy; Encapsulated; Endosomes; Exocytosis; Exposure to; Feedback; Fetal Membranes; Fetal Tissues; Fetus; Flow Cytometry; Genes; Genetic Transcription; HMGB1 Protein; Human; Immune response; Immunoblotting; Inflammation; Inflammatory; Knowledge; Labor Onset; Lead; Liquid substance; MAP Kinase Gene; MAPK14 gene; Mediating; Metabolic; Molecular; Mothers; Muscle Cells; Myometrial; Organ Culture Techniques; Oxidants; Oxidative Stress; PTGS2 gene; Pathway interactions; Peripheral; Pharmacology; Phenotype; Physiological; Plasma; Pregnancy; Pregnancy Outcome; Pregnancy Tests; Premature Birth; Premature Labor; Premature aging syndrome; Process; Progesterone; Progesterone Receptors; Protein Isoforms; Proteins; Public Health; RNA Interference; Reaction; Recombinants; Research; Risk; Risk Factors; Role; Signal Transduction; Sterility; Stimulus; TLR2 gene; TLR4 gene; Term Birth; Testing; Tissues; Toll-like receptors; Up-Regulation; Venous; Vesicle; Withdrawal; aged; amnion; base; clinical material; cytokine; cytotrophoblast; exosome; experimental study; fetal; fetus cell; mitogen-activated protein kinase p38; myometrium; non-histone protein; novel; novel therapeutics; particle; prevent; progesterone receptor A; progesterone receptor B; public health relevance; receptor; response; senescence; therapy design; trophoblast

 DESCRIPTION (provided by applicant): Fetal cell senescence at term is a natural physiologic response to oxidative stress (OS) that occurs as a result of increased metabolic demands by the maturing fetus. Various risk factors for preterm labor are associated with OS-induced senescence. Our pilot data suggest that fetal cell senescence causes the alarmin HMGB1 (a non-histone protein) to translocate from the nucleus to the cytosol. There it is modified by acetylation and released via exocytosis ("free" HMGB1) or encapsulated in exosomes, (30-100 nm particles) formed and extruded by multivesicular endosome fusion with the plasma membrane. Secreted HMGB1 functions as a proinflammatory cytokine in feto-maternal tissues. In the fetal membranes, it augments fetal cell senescence and an associated 'sterile' inflammatory reaction through TLR2-mediated p38 MAPK activation. In myocytes, HMGB1 activates p38 MAPK, resulting in upregulation of progesterone receptor (PR) isoform A and increased COX-2 expression and myocyte inflammation. A positive OS feedback loop is also established by HMGB1, accelerating amniocyte aging. Our core hypothesis posits that HMGB1 secreted from senescing fetal membranes, either by diffusion or transported via exosomes, causes myometrial activation through p38 MAPK, which in turn increases the ratio of PR-A to PR-B, leading to functional progesterone withdrawal and triggering the onset of labor. This hypothesis will be tested in 2 specific aims. Specific Aim 1 will determine how OS stimulates fetal membrane cell-derived HMGB1 secretion, as free protein or packaged and exported in exosomes, during human pregnancy and parturition. Specific Aim 2 will determine how free- or exosome-HMGB1 produced by fetal membrane cells in response to OS induces functional progesterone withdrawal and myometrial contractility. Primary and transformed human amnion, chorionic trophoblast, and myometrial cells, as well as fetal membrane and myometrial organ cultures, will be exposed to OS-inducing agents. Using molecular and cellular biological approaches we will quantitate OS-induced fetal cell senescence, HMGB1 release, exosome packaging, direction of exosome-HMGB1 secretion, signaling via p38 MAPK, PR isoform switching, and myometrial activation. Additionally, we will quantify the concentrations of exosome-HMGB1 in our banked feto-maternal biologic fluids (amniotic fluid, peripheral and maternal uterine venous plasma, and fetal cord plasma) from term and preterm births (PTB) to correlate their distribution with defined pregnancy outcomes. This study will evaluate a new feto-maternal signaling mechanism that triggers parturition in response to fetal OS. Identification of novel pathways and biomolecules should provide new targets to screen, diagnose, and reduce the risk of PTB.