UC Davis Conte Center: Neuroimmune Mechanisms of Psychiatric Disorders

加州大学戴维斯分校康特中心：精神疾病的神经免疫机制

• 批准号: 10592299
• 负责人: Cameron S. Carter
• 金额: $ 312.2万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592299
• 关键词: Address; Adolescence; Affect; Age; Age Months; Behavioral; Biological Markers; Brain; COVID-19 pandemic; Cells; Cognitive; Computer Models; Corpus striatum structure; Coupled; Development; Diffusion Magnetic Resonance Imaging; Disease; Dopamine; Early Intervention; Female; Functional Magnetic Resonance Imaging; Funding; Gene Expression; Genomics; Heterogeneity; Human; Image; Immune; Immune response; Immune signaling; Incidence; Individual; Infection; Intervention; Knowledge; Lead; Link; Magnetic Resonance Spectroscopy; Maternally-Acquired Immunity; Measures; Mediating; Mental disorders; Modeling; Molecular; Mothers; Motivation; Mus; Neuroanatomy; Neurodevelopmental Disorder; Neuroimmune; Neuroimmunomodulation; Outcome; Pathway interactions; Patients; Phenotype; Poly I-C; Population; Predisposition; Pregnancy; Psychopathology; Research; Research Personnel; Risk; Risk Factors; Rodent Model; Schizophrenia; Sex Differences; Signal Pathway; Symptoms; Testing; Therapeutic Intervention; Time; at-risk pregnancies; behavioral outcome; behavioral phenotyping; biological sex; biomarker development; brain abnormalities; clinically relevant; cognitive control; immune activation; immunoreactivity; in vivo; male; maternal immune system; mouse model; neural; neural circuit; neuroimaging; neuromelanin; neuropsychiatric disorder; non-genetic; nonhuman primate; novel therapeutics; offspring; optogenetics; outcome prediction; postnatal period; predictive modeling; prevent; resilience; response; schizophrenia risk; sex; sobriety; therapy development; transcriptomics; young adult

PROJECT SUMMARY - OVERALL Psychiatric illnesses, including schizophrenia, affect a significant proportion of the population, yet current treatments are only partially effective for many individuals and, in the case of SZ, do little to address disabling cognitive and negative symptoms. Thus, there is a pressing need to develop biomarkers to identify at-risk individuals for early intervention and new molecular pathways to target for development of novel therapies. An increasingly compelling pathway associated with SZ is immune dysregulation. This proposed renewal of the UC Davis Conte Center brings together investigators with a unique combination and wide range of complementary expertise to address a critical gap in knowledge related to the potential links between immune dysregulation and psychiatric illness. During the previous funding period, we took a multi-pronged approach to test our Center hypothesis that early activation of the maternal immune system alters brain development in offspring leading to structural and functional changes in connectivity that are associated with the emergence of psychopathology in adolescence and young adulthood. Four important findings emerged from those studies that serve as the premise for this renewal application. First, we discovered two factors in the mouse model that predict susceptibility and resilience of offspring to MIA, allowing us to study why MIA causes aberrant outcomes in only a subset of pregnancies and how it can lead to diverse phenotypes in offspring. Second, we found signatures of abnormal brain development in our male MIA NHP offspring as early as 6 months of age, indicating that the early postnatal period is critical for understanding the impact of MIA on brain development. Third, combined results from NHP and mouse models point to cortico-striatal circuitry as central to behavioral outcomes in MIA offspring. Finally, convergence between MIA NHP imaging findings and recent onset SZ support the clinical relevance of the MIA models. In this renewal, we will continue to test our original Center hypothesis across species (mouse and NHP MIA models and humans with SZ), through three specific aims: (i) Identify immune signaling pathways in females before and during pregnancy that confer susceptibility or resilience to distinct subsets of MIA-induced behavioral phenotypes in offspring, (ii) Determine the contribution of cortico-striatal circuits to susceptibility, resilience and phenotypic heterogeneity in MIA mouse and NHP offspring and in individuals with SZ, and (iii) Determine how sex contributes to susceptibility, resilience and phenotypic heterogeneity in MIA offspring and individuals with SZ. Successful completion of these Aims, which could only be accomplished in a highly integrated interdisciplinary Center as proposed, will identify causal molecular pathways in specific neural circuits critical for guiding the development of interventions optimized for the developmental age and sex of at-risk offspring following MIA. They will also reveal new immune signaling pathways that can be targeted for the development of biomarkers to identify at- risk pregnancies, and a new class of much-needed therapeutic interventions to prevent SZ and other NDDs.

项目概要 - 总体 包括精神分裂症在内的精神疾病影响着很大一部分人口，但目前 治疗对许多人来说仅部分有效，并且就 SZ 而言，对于解决残疾问题几乎没有作用 认知和阴性症状。因此，迫切需要开发生物标志物来识别高危人群 个人进行早期干预和新分子途径，以开发新疗法为目标。一个 与 SZ 相关的越来越引人注目的途径是免疫失调。此次提议的更新 加州大学戴维斯分校康特中心汇集了具有独特组合和广泛范围的研究人员 互补的专业知识，以解决与免疫之间潜在联系相关的知识的关键差距 失调和精神疾病。在上一个融资期间，我们采取了多管齐下的方式 测试我们中心的假设，即母体免疫系统的早期激活会改变大脑发育 在后代中导致与相关的连接结构和功能的变化 精神病理学在青春期和成年早期的出现。出现了四个重要发现 来自那些作为本次更新申请前提的研究。首先我们发现了两个因素 预测后代对 MIA 的易感性和恢复力的小鼠模型，使我们能够研究 MIA 的原因 仅在一小部分妊娠中出现异常结果，以及它如何导致后代出现不同的表型。 其次，我们早在 6 岁时就在 MIA NHP 雄性后代中发现了大脑发育异常的特征 月龄，表明产后早期对于了解 MIA 对大脑的影响至关重要 发展。第三，NHP 和小鼠模型的综合结果表明皮质纹状体回路是中枢 MIA 后代的行为结果。最后，MIA NHP 成像结果与最近的研究结果之间的趋同 起始 SZ 支持 MIA 模型的临床相关性。在本次更新中，我们将继续测试我们原来的 跨物种（小鼠和 NHP MIA 模型以及患有 SZ 的人类）的中心假设，通过三个特定的 目标：(i) 确定女性怀孕前和怀孕期间赋予易感性的免疫信号通路 或对子代 MIA 诱导的行为表型的不同子集的恢复能力，(ii) 确定 皮质纹状体回路对 MIA 小鼠易感性、弹性和表型异质性的贡献 和 NHP 后代以及 SZ 个体，以及 (iii) 确定性别如何影响易感性， MIA 后代和 SZ 个体的恢复力和表型异质性。顺利完成 这些目标只能在所提议的高度一体化的跨学科中心才能实现， 识别特定神经回路中对于指导发展至关重要的因果分子途径 针对 MIA 后高危后代的发育年龄和性别优化干预措施。他们还将 揭示新的免疫信号通路，可用于开发生物标志物来识别- 风险怀孕，以及急需的一类新的治疗干预措施来预防 SZ 和其他 NDD。