Neurodevelopment of Tourette syndrome

抽动秽语综合症的神经发育

• 批准号: 10529308
• 负责人: FLORA M VACCARINO
• 金额: $ 42.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-19 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529308
• 关键词: Anatomy; Architecture; Astrocytes; Autopsy; Basal Ganglia; Biological Markers; Blood specimen; Brain; Calcium Channel; Cell Line; Cell Nucleus; Cells; ChIP-seq; Child; Chronic; Clinical Trials; Clinical assessments; Complex; Corpus striatum structure; Development; Disease; Disease model; Disease remission; Electrophysiology (science); Enhancers; Environmental Risk Factor; Epigenetic Process; Fluorescence; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Enhancer Element; Gilles de la Tourette syndrome; Heritability; Human; Immune; Immunologics; In Vitro; Individual; Inflammatory; Interneurons; Longitudinal cohort study; Maps; Metabolic; Metabolism; Microglia; Modeling; Molecular; Mutation; Neurobiology; Neuroglia; Neuronal Differentiation; Neurons; Nitric Oxide Synthase; Nuclear; Oligodendroglia; Organoids; Outcome; Parvalbumins; Pathway Analysis; Pathway interactions; Patients; Pattern; Potassium Channel; Predisposing Factor; Recurrence; Research Personnel; Somatostatin; Sorting; Subgroup; Synapses; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Transcript; Variant; Work; autism spectrum disorder; brain tissue; cell type; cholinergic; cholinergic neuron; chromatin immunoprecipitation; clinical biomarkers; epigenome; epigenomics; experimental study; follow-up; gamma-Aminobutyric Acid; gene network; gene regulatory network; genetic variant; genome-wide; immunocytochemistry; induced pluripotent stem cell; longitudinal analysis; mind control; morphogens; network dysfunction; neural; neurodevelopment; neuroimaging; neuropeptide Y; neuropsychiatric disorder; neurotransmission; proband; progenitor; putamen; recruit; response; stem cell model; transcriptome; transcriptome sequencing; transcriptomic profiling; transcriptomics

Tourette syndrome (TS) is a common disorder that afflicts as many as 1 in 150 children. Despite the high familiar recurrence rate, no significant causative or predisposing factor has yet emerged in TS. Neuroimaging and anatomical studies have implicated the striatum within the basal ganglia in TS. In postmortem brain tissue of patients with severe TS we found a decrease in striatal cholinergic neurons (CH/TAN) and two types of GABA interneurons, the parvalbumin+ (PV) and Somatostatin/Nitric Oxide Synthase /Neuropeptide Y+ (SST/NOS/NPY) by immunocytochemistry. Transcriptome profiling by RNA sequencing highlighted a decrease in synaptic neurotransmission and metabolism-related biofunctions in TS, as well as a prominent increase in inflammatory transcripts, as compared to matched normal controls (NC) brains. However, these signatures are an average of a complex cellular mixture and most likely miss changes occurring in cell subpopulations, particularly interneurons. We now seek to identify the transcriptome of striatal medium spiny neuron (MSN), interneuron (INT), astrocytes & microglia (AST/MICR) and oligodendrocytes (OLIG) cell subpopulations by fluorescence-activated nuclear sorting (FAN) as well as single neuronal nuclei in TS and NC postmortem brain tissue. Correspondingly, the epigenome of these cell types will be characterized by chromatin immunoprecipitation and sequencing (ChIP-seq) in the same cellular fractions. Differentially active enhancer regions will be mapped in the striatum of TS vs NC and a gene regulatory network encompassing changes in gene expression and corresponding enhancer activities will be built. Network modules differentially active in TS will be used to construct a model of dysfunctional striatal circuitry in TS. To understand the origin and potential causes of this network dysfunction, we will recapitulate early telencephalic development in vitro using a human induced pluripotent stem cell (iPSC) model of the disorder. Basal ganglia and cortical organoids from chronic TS patients, recovered TS patients and NC will be longitudinally analyzed and compared on the cellular, transcriptomic, epigenomic and electrophysiological levels to reveal cell fate, neuronal differentiation, molecular and functional abnormalities that underlie the disorder and its outcome. These complementary experiments will define the likely time of origin, pathophysiology, and molecular underpinnings of TS and provide a disease model where genetic and epigenetic changes can be perturbed to assess their neurobiological effects.

图雷特综合症（TS）是一种常见的疾病，每150名儿童中就有1名患有此病。尽管高

项目成果

Role of SHH in Patterning Human Pluripotent Cells towards Ventral Forebrain Fates.

• DOI: 10.3390/cells10040914
• 发表时间: 2021-04-16
• 期刊: Cells
• 影响因子: 6
• 作者: Brady MV;Vaccarino FM
• 通讯作者: Vaccarino FM

Antibodies From Children With PANDAS Bind Specifically to Striatal Cholinergic Interneurons and Alter Their Activity.

• DOI: 10.1176/appi.ajp.2020.19070698
• 发表时间: 2021-01-01
• 期刊: The American journal of psychiatry
• 作者: Xu J;Liu RJ;Fahey S;Frick L;Leckman J;Vaccarino F;Duman RS;Williams K;Swedo S;Pittenger C
• 通讯作者: Pittenger C

Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability.

• DOI: 10.1126/science.abm6222
• 发表时间: 2022-07-29
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Bae, Taejeong;Fasching, Liana;Wang, Yifan;Shin, Joo Heon;Suvakov, Milovan;Jang, Yeongjun;Norton, Scott;Dias, Caroline;Mariani, Jessica;Jourdon, Alexandre;Wu, Feinan;Panda, Arijit;Pattni, Reenal;Chahine, Yasmine;Yeh, Rebecca;Roberts, Rosalinda C.;Huttner, Anita;Kleinman, Joel E.;Hyde, Thomas M.;Straub, Richard E.;Walsh, Christopher A.;Network, Brain Somatic Mosaicism;Urban, Alexander E.;Leckman, James F.;Weinberger, Daniel R.;Vaccarino, Flora M.;Abyzov, Alexej
• 通讯作者: Abyzov, Alexej

Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids.

• DOI: 10.1038/s41380-022-01880-5
• 发表时间: 2022-12
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Brady, Melanie V.;Mariani, Jessica;Koca, Yildiz;Szekely, Anna;King, Robert A.;Bloch, Michael H.;Landeros-Weisenberger, Angeli;Leckman, James F.;Vaccarino, Flora M.
• 通讯作者: Vaccarino, Flora M.