Novel mechanisms underlying the impact of prenatal stress on neurodevelopment

项目摘要/摘要 这个职业发展奖的目标是询问产前应激、胎盘 微生物、宫内炎症和生长因子，并探讨它们对子宫内膜异位症发生的影响。 暴露的后代的异常行为。这项建议旨在促进职业发展和 向独立过渡的Tamar L.Gur，医学博士，董事会认证，执业精神病学家，专业 治疗围产期抑郁症和焦虑症。在颁奖结束时，古尔博士将成为 独立调查员，领导一个跨学科的研究实验室，将使 有助于理解产前应激对后代精神障碍的影响 探讨宫内应激、微生物、炎症和生长因子的相互作用 环境，使用创新的方法。Gur博士将通过她的联合指导获得这方面的专业知识 主要导师迈克尔·贝利博士，压力和微生物组领域的领导者，以及共同导师伊琳娜博士 Buhimschi医学博士，孕期病理生理学的分子机制专家，和小鼠 怀孕的模特儿。已知，产前应激是导致老年人出现精神疾病的原因之一。 后代。这项拟议的研究将研究孕期应激的基本机制。 通过研究胎盘微生物的功能，并确定如何改变 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。 Gur博士已经建立了一个产前应激的小鼠模型，这种模型会导致胎盘微生物和 子宫内炎症和脑源性神经营养因子的伴随变化，导致 女性的焦虑和认知变化，男性社交行为的减少，以及长期的 两性都有微生物群。据我们所知，这是第一个产前应激改变微生物的证据。 子宫。我们的假设是，胎盘中的生物失调改变了炎症和脑源性神经营养因子，影响了发育 中枢神经系统，导致子代长期的微生物群和行为变化。这 假设将通过追求以下目标来检验：1)确定胎盘微生物是否有活力，他们的 来源，以及利用无菌小鼠模型，它们是否足以引起行为变化；2) 确定母亲应激是否与宫内环境中的免疫失调有关；3) 确定应激诱导的微生物区系变化如何改变子宫内的BDNF。古尔博士已经组装了一个 优秀的导师团队，包括压力和炎症方面的先驱，以及微生物和健康方面的先驱。这个 俄亥俄州立大学的广泛资源以及她所在部门和 与她在统计学教学方面的正式计划一起，将进一步支持古尔博士阐明 产前应激对发育中后代影响的潜在机制。

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.