Novel mechanisms underlying the impact of prenatal stress on neurodevelopment

产前应激对神经发育影响的新机制

• 批准号: 9295512
• 负责人: Tamar Gur
• 金额: $ 18.72万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295512
• 关键词: Address; Adult; Adult Children; Amniotic Fluid; Anxiety; Attention; Autistic Disorder; Award; Bacteria; Behavior; Behavioral; Behavioral Paradigm; Biological Factors; Brain; Brain-Derived Neurotrophic Factor; CCL2 gene; Career Mobility; Childhood; Chronic Disease; Communities; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Environment; Epigenetic Process; Epithelial; Exposure to; Female; Functional disorder; Gastrointestinal tract structure; Germ-Free; Goals; Growth Factor; Gur; Health; High-Throughput Nucleotide Sequencing; Hippocampus (Brain); Hormones; Human; Immune; Immune response; Infant; Inflammation; Inflammatory; Institutes; Interdisciplinary Study; Interleukin-6; K-Series Research Career Programs; Knowledge; Laboratory Research; Leukocytes; Link; Mental Depression; Mental disorders; Mentors; Methods; Microbe; Molecular; Mus; Neuraxis; Neurobiology; Neurodevelopmental Disorder; Ohio; Oral cavity; Placenta; Play; Pregnancy; Premature Birth; Prevalence; Process; Production; Psychiatrist; Recruitment Activity; Regulation; Research; Research Personnel; Resources; Risk; Rodent Model; Role; Schizophrenia; Sex Characteristics; Social Behavior; Sterility; Stress; Surface; Symbiosis; Testing; Universities; Volatile Fatty Acids; anxiety-like behavior; behavioral response; career development; chemokine; cognitive change; cytokine; design; epigenetic regulation; in utero; inflammatory marker; innovation; male; maternal serum; maternal stress; microbiome; microbiota; mouse model; negative affect; neonatal exposure; neurodevelopment; next generation; novel; novel strategies; offspring; peripartum depression; prenatal; prenatal influence; prenatal stress; reproductive tract; sex; statistics; stressor

PROJECT SUMMARY/ABSTRACT The goal of this career development award is to interrogate the relationship between prenatal stress, placental microbes, intrauterine inflammation and growth factors, and investigate their influence on the development of aberrant behavior in exposed offspring. The proposal is designed to facilitate the career development and transition to independence of Tamar L. Gur, M.D., Ph.D., a board certified, practicing psychiatrist, specializing in the treatment of perinatal depression and anxiety. At the conclusion of the award, Dr. Gur will be an independent investigator, leading a transdisciplinary research laboratory that will make substantial contributions to the understanding of the influence of prenatal stress on psychiatric disorders in offspring, by probing the interplay between stress, microbes, inflammation and growth factors in the intrauterine environment, using innovative methods. Dr. Gur will gain this expertise through the combined guidance of her primary mentor, Dr. Michael Bailey, PhD, a leader in stress and the microbiome, and co-mentor, Dr. Irina Buhimschi, MD, an expert in the molecular mechanisms underlying pathophysiology in pregnancy, and mouse models of pregnancy. Prenatal stress is a known contributor to the emergence of psychiatric illness in the offspring. The proposed research will examine basic mechanisms underlying the contribution of prenatal stress to psychiatric disorders by investigating the function of placental microbes, and to determine how alterations in these microbes contributes to inflammation and regulation of growth factors in the intrauterine environment. Dr. Gur has established a mouse model of prenatal stress, which induces alterations in placental microbes and concomitant changes in inflammation and brain derived neurotrophic factor in utero, resulting in increased anxiety and cognitive changes in females, decreased social behavior in males, and longstanding changes in microbiome in both sexes. To our knowledge, this is the first evidence that prenatal stress alters microbes in utero. Our hypothesis is that dysbiosis in the placenta alters inflammation and BDNF, impacting the developing central nervous system, resulting in long-term microbiome and behavioral changes in the offspring. This hypothesis will be tested by pursuing these aims: 1) Determine whether placental microbes are viable, their origin, and, utilizing a germ-free mouse model, whether they are sufficient to induce behavioral changes; 2) Determine whether maternal stress is associated with immune dysregulation in the intrauterine environment; 3) Determine how stress-induced changes in microbiota alter BDNF in utero. Dr. Gur has assembled an outstanding team of mentors, including pioneers in stress and inflammation, and microbiome and health. The extensive resources of the Ohio State University and deep commitment and support of her Department and Institute, together with her formal plan for didactics in statistics, will further support Dr. Gur's goal of elucidating the mechanisms underlying the impact of prenatal stress on the developing offspring.

项目总结/摘要 这个职业发展奖的目标是询问产前压力，胎盘， 微生物，宫内炎症和生长因子，并探讨其对发展的影响， 暴露后代的异常行为该提案旨在促进职业发展， 过渡到独立的添马舰L。Gur，医学博士，哲学博士、一个委员会认证的执业精神病医生， 治疗围产期抑郁症和焦虑症在颁奖结束时，古尔博士将是一个 独立调查员，领导一个跨学科的研究实验室，将使大量的 有助于了解产前压力对后代精神疾病的影响， 探索子宫内压力，微生物，炎症和生长因子之间的相互作用 环境，创新方法。古尔博士将通过她的联合指导， 主要导师Michael Bailey博士，压力和微生物组的领导者，以及共同导师Irina博士 Buhimschi博士是妊娠病理生理学分子机制方面的专家， 怀孕的模型。产前压力是一个已知的贡献者出现的精神疾病， 后代这项拟议中的研究将探讨产前压力的基本机制 通过研究胎盘微生物的功能，并确定 这些微生物有助于子宫内环境中的炎症和生长因子的调节。 博士古尔建立了一个产前应激的小鼠模型，该模型诱导胎盘微生物的改变， 炎症和脑源性神经营养因子在子宫内的伴随变化，导致增加 女性的焦虑和认知变化，男性的社会行为减少， 两性的微生物组。据我们所知，这是第一个证据表明，产前压力改变了微生物， 子宫。我们的假设是，胎盘中的生态失调改变了炎症和BDNF，影响了发育中的 中枢神经系统，导致后代的长期微生物组和行为变化。这 将通过追求这些目标来测试假设：1）确定胎盘微生物是否存活， 来源，以及利用无菌小鼠模型，它们是否足以诱导行为变化; 2） 确定母体压力是否与宫内环境中的免疫失调有关; 3） 确定压力诱导的微生物群变化如何改变子宫内的BDNF。古尔博士已经召集了一个 杰出的导师团队，包括压力和炎症，微生物组和健康方面的先驱。的 俄亥俄州州立大学的广泛资源和她的部门的坚定承诺和支持， 研究所，连同她的正式计划，教学统计，将进一步支持古尔博士的目标，阐明 产前压力对发育中后代影响的潜在机制。