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Cell-specific analysis of sub-kinomes in schizophrenia

精神分裂症亚激酶组的细胞特异性分析

基本信息

批准号：
9926312
负责人：
JAREK MELLER
金额：
$ 33.96万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9926312
关键词：
Address Adverse effects Anatomy Antipsychotic Agents Astrocytes Autopsy Basal Ganglia Biochemical Bioinformatics Biological Biological Assay Brain Brain region Cells Climacteric Clozapine Cognitive Cognitive deficits Consensus Corpus striatum structure Coupling Cyclic AMP-Dependent Protein Kinases Data Databases Delusions Development Disease Disinhibition Dopamine Antagonists Dopamine D2 Receptor Drug Targeting Elements Environment Environmental Risk Factor Equilibrium Expression Profiling Failure Functional disorder Gene Expression Genes Genetic Predisposition to Disease Genetic Transcription Goals Hallucinations Interneurons Intervention Lead Lesion Libraries Measures Medicine Messenger RNA Modeling Molecular Motivation Network-based Neurobehavioral Manifestations Neuronal Plasticity Neurons Neuropil Parvalbumins Pathologic Pathway interactions Persons Pharmaceutical Preparations Pharmacological Treatment Pharmacology Phenotype Phosphoproteins Phosphotransferases Population Prefrontal Cortex Protein Kinase Proteomics Proto-Oncogene Proteins c-akt Pyramidal Cells Rodent Sampling Schizophrenia Serine Short-Term Memory Signal Pathway Signal Transduction Standardization Symptoms Synaptic Transmission Synaptic plasticity Techniques Testing Thalamic structure Threonine Vertebral column atypical antipsychotic base brain tissue cell type cognitive task comparison group density disability drug development executive function experimental study follow-up frontal lobe hippocampal pyramidal neuron in silico innovation knock-down laser capture microdissection migration myelination network models neurotransmission new therapeutic target novel novel therapeutics severe mental illness side effect small molecule treatment strategy young adult

项目摘要

Project Summary: This is a revised R01 application to investigate abnormalities of signaling networks in pyramidal neurons in schizophrenia. It is an understatement to say that the treatment of schizo-spectrum disorders has not progressed in the past 25 years, since the development of atypical antipsychotics. However, there is broad consensus that these newer medications do not extend the efficacy of pharmacological treatments to cognitive and negative/deficit symptoms, which lead to profound disability in a large number of persons afflicted with schizophrenia. While effective for the psychotic, or positive symptoms, all antipsychotic medications are associated with significant side effects, and have high rates of discontinuation. We posit that abnormalities of cortical pyramidal neurons underlie many of the cognitive deficits observed in the schizophrenia phenotype, including abnormalities of working memory, executive function, and motivation. Pyramidal neurons typically project to other cortical regions (superficial pyramidal cells, in layers II and III) or subcortically (deep pyramidal cells, in layers V and VI) to the thalamus, striatum, and other basal ganglia. Divergent abnormalities of superficial and deep pyramidal neurons in schizophrenia may arise from neurodevelopmental insults that reflect differences in the circuitry of these cell types, resulting in altered gene expression profiles, neuronal migration, and/or aberrant connectivity of these neurons. We hypothesize that abnormalities of pyramidal neurons extend well beyond simple measures of gene expression, and include disease- and lamina- specific changes in functionally related signaling networks. To address this problem, we adapted a novel “omics” bioinformatics approach for analysis of serine/threonine sub-kinomes in postmortem brain tissue, and identified high-yield protein kinase targets for further study. We propose to focus in this application on two of our high- yield “hits” from these hypothesis generating preliminary studies: AKT and PKA. Specifically, we will test the hypothesis that these kinases are differentially regulated in superficial and deep pyramidal neurons in schizophrenia. We will use an innovative approach that combines standard techniques, including laser capture microdissection and biochemical kinase activity assays, to measure pyramidal neuron-specific kinase expression and activity in schizophrenia. We will follow up on these studies by measuring expression of factors downstream from AKT and PKA, including phosphoproteins and related networks of mRNAs. Finally, we propose two discrete in silico studies, one focused on developing pyramidal neuron-specific signaling models in schizophrenia, and the other focused on integration of our data with cutting-edge bioinformatics databases, to identify pathways associated with standardized pathophysiological disease-drug dyads. These innovative studies will identify pyramidal neuron-specific signaling pathways disrupted in schizophrenia and provide new ideas regarding the pathophysiology and the development of novel treatment strategies for this often devastating illness.

项目总结:

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gene Enrichment Analysis of Astrocyte Subtypes in Psychiatric Disorders and Psychotropic Medication Datasets.

DOI：
10.3390/cells11203315
发表时间：
2022-10-21
期刊：
CELLS
影响因子：
6
作者：
Zhang, Xiaolu;Wolfinger, Alyssa;Wu, Xiaojun;Alnafisah, Rawan;Imami, Ali;Hamoud, Abdul-rizaq;Lundh, Anna;Parpura, Vladimir;McCullumsmith, Robert E.;Shukla, Rammohan;O'Donovan, Sinead M.
通讯作者：
O'Donovan, Sinead M.

Altered purinergic receptor expression in the frontal cortex in schizophrenia.

DOI：
10.1038/s41537-022-00312-1
发表时间：
2022-11-14
期刊：
SCHIZOPHRENIA
影响因子：
0
作者：
Alnafisah, Rawan;Lundh, Anna;Asah, Sophie M.;Hoeflinger, Julie;Wolfinger, Alyssa;Hamoud, Abdul-Rizaq;McCullumsmith, Robert E.;O'Donovan, Sinead M.
通讯作者：
O'Donovan, Sinead M.