Vitamin-D- PRODH- & DTNBP1-Induced Hyperprolinemia:Schizophrenia Risk & Treatment

维生素-D-PRODH-

• 批准号: 8632387
• 负责人: CATHERINE L CLELLAND
• 金额: $ 50.46万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632387
• 关键词: 2,4-thiazolidinedione; 22q11; 22q11.2; 22q11.21; Adult; Amino Acids; Amphetamines; Animals; Astrocytes; Attenuated; Behavioral; Biological; Biological Assay; Biological Models; Blood; Brain; Catabolism; Chromosomes; Cognitive; Cognitive deficits; Cohort Studies; Data; Development; Diet; Dopamine; Enzymes; Exhibits; Fasting; Figs - dietary; Gene Expression; Gene Mutation; Genes; Genetic Risk; Genetic Variation; Genomics; Glutamates; Hippocampus (Brain); Human; Hypersensitivity; Impaired cognition; Impairment; Influentials; Intervention; Lead; Learning; Link; Measures; Mediating; Memory impairment; Modeling; Molecular; Molecular Abnormality; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Neonatal; Neuromodulator; Neurons; Neurotransmitters; Outcome; Pathway interactions; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phenotype; Plasma; Primary Cell Cultures; Proline; Proline Dehydrogenase; Public Health; Relative (related person); Reporting; Risk; Risk Factors; Sampling; Schizophrenia; Short-Term Memory; Signal Transduction; Source; Study Section; Supplementation; Symptoms; Synapses; Testing; Thiazolidinediones; Tissues; Toxic effect; Up-Regulation; Variant; Vitamin D; Vitamin D2; Work; cohort; design; early childhood; endophenotype; functional restoration; gamma-Aminobutyric Acid; genetic variant; in vivo; in vivo Model; microdeletion; mouse model; null mutation; prepulse inhibition; prevent; public health relevance; response; restoration; rosiglitazone; screening

PROJECT SUMMARY The highest known genetic risk of schizophrenia (SZ) is conferred by hemizygous microdeletion of chromosome 22q11. The proline dehydrogenase gene (PRODH) is located in the common deleted region, and encodes the enzyme that catalyzes proline catabolism. Proline is a neuromodulator at glutamatergic synapses, and the peripheral hyperprolinemia arising from PRODH mutations or CNVs encompassing PRODH, has been associated with cognitive impairment and decreased IQ. We recently reported a highly significant association of hyperprolinemia with SZ. We now provide evidence that two further independent SZ risk factors: Low vitamin-D status, and mutation of the dysbindin gene (Dtnbp1), also cause hyperprolinemia. Our findings suggest convergence of the biological pathways regulated by vitamin-D and DTNBP1, via loss of PRODH expression, with elevated proline as a common SZ endophenotype. Studies have documented the dysfunctional consequences of hyperprolinemia, such as aberrant glutamatergic and dopamine signaling leading to, for example, cognitive deficits and attenuated prepulse inhibition (PPI). Targeting hyperprolinemia in the Dtnbp1 model may therefore positively impact neurotransmitter signaling and restore function. This proposed study is designed to test our hypotheses under the following Specific Aims. Aim 1: To test the relative molecular contributions of low Vitamin D, and PRODH, and DTNBP1 gene variants, to SZ- associated hyperprolinemia. In a SZ patient and control sample (n=250), we will measure plasma proline and Vitamin-D levels, confirming the strong relationship between elevated proline and low Vitamin-D. From our preliminary data, we anticipate that 80% of the measured hyperprolinemia will arise from low vitamin-D, while DTNBP1 and PRODH variants will be responsible for the remaining 20%. Thus, we will perform molecular analyses on our complete study cohort (404 subjects), screening for PRODH, and DTNBP1 variants that alter gene expression, and testing for variant associations, plus interactions with low Vitamin-D, on the outcome of proline elevation. Aim 2: To examine the molecular pathway leading to hyperprolinemia in the Dtnbp1 model. Aim 2A. Molecular analyses will include assay of peripheral and CNS tissue expression of Prodh, p53 regulated genes, and Comt (downstream of Prodh), as well as of cortical, hippocampal and peripheral proline levels. Aim 2B. Utilizing primary neurons and astrocytes from sdy-/- and Prodh+/- mice, we will directly upregulate Prodh expression, via treatment with Vitamin D and the thiazolidinedione drug Rosiglitazone (RZG), testing for restoration of Prodh expression and decreased cellular proline. Aim 3: To target hyperprolinemia in the Dtnbp1 model in vivo. We will examine whether treatment with Vitamin D (Aim 3a), RZG (Aim 3b), and, to seek to reduce the impact of off-target effects, a proline-deficient diet (Aim 3c), compared to vehicle- treatment alone, restores the above pathway in vivo, and prevents or alleviates the Sdy-/- deficit in, for example, PPI and spatial working memory.

项目总结 已知的精神分裂症(SZ)的最高遗传风险是由于半合子基因的微缺失 染色体22q11。Pro脱氢酶基因(PROSH)位于常见的缺失区， 编码催化脯氨酸分解代谢的酶。脯氨酸是谷氨酸能突触的神经调节剂， 和外周高脯氨酸血症引起的PROSH突变或围绕PROSH的CNV，已被 与认知障碍和智商下降有关。我们最近报道了一个非常重要的关联 伴有SZ的高脯氨酸血症。我们现在提供了两个进一步独立的SZ风险因素的证据：低 维生素D状态和dybindin基因突变(Dtnbp1)也会导致高脯氨酸血症。我们的发现 提示受维生素D和DTNBP1调控的生物通路通过PRODH的丢失而趋同 表达，以升高的脯氨酸为常见的SZ内表型。研究已经记录了 高脯氨酸血症的功能障碍后果，如谷氨酸和多巴胺信号异常 例如，导致认知缺陷和减弱的脉搏前抑制(PPI)。靶向高脯氨酸血症 因此，Dtnbp1模型可能会对神经递质信号转导和恢复功能产生积极影响。 这项拟议的研究旨在以下特定目标下检验我们的假设。目标1：测试 低维生素D、PROSH和DTNBP1基因变异对SZ的相对分子贡献 伴发的高脯氨酸血症。在SZ患者和对照样本(n=250)中，我们将测定血浆脯氨酸 和维生素D水平，证实了脯氨酸升高和低维生素D之间的强烈关系。从我们的 初步数据显示，我们预计80%的高脯氨酸血症是由低维生素D引起的，而 DTNBP1和PROSH变种将负责剩余的20%。因此，我们将执行分子 对我们的完整研究队列(404名受试者)进行分析，筛查PROSH和改变的DTNBP1变体 基因表达，变异关联的测试，以及与低维生素D的相互作用，对结果的影响 Pro高程。目的2：研究Dtnbp1中导致高脯氨酸血症的分子途径 模特。目标2 A。分子分析将包括检测外周和中枢神经系统组织中PROSH、P53的表达 调节基因，以及COMT(PROH下游)，以及皮质、海马区和外周区的脯氨酸 级别。目标2B。利用SDY-/-和PROSH+/-小鼠的原代神经元和星形胶质细胞，我们将直接 通过维生素D和噻唑烷二酮类药物罗格列酮(RZG)的治疗，上调PROSH的表达， 检测是否恢复了PROHH的表达，并降低了细胞内的脯氨酸。目标3：瞄准高脯氨酸血症 在体内的Dtnbp1模型中。我们将检查维生素D(目标3a)、RZG(目标3b)、 而且，为了减少偏离目标的影响，与载体相比，缺乏脯氨酸的饮食(目标3c)。 单独治疗，在体内恢复上述途径，防止或缓解SDY-/-缺陷。 例如，PPI和空间工作记忆。