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

维生素-D-PRODH-

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要精神分裂症（SZ）的最高遗传风险是通过半合子微碎片赋予的染色体22q11。脯氨酸脱氢酶基因（PODH）位于公共缺失区域，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，并且由PRODH突变或CNV引起的周围性高脱位，包括prodh 与认知障碍和智商减少有关。我们最近报道了非常重要的关联患有SZ的高脱脂血症。现在，我们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dysbindin基因的突变（DTNBP1）也会引起高丙纤维血症。我们的发现建议通过损失VODH的维生素-D和DTNBP1调节的生物学途径收敛表达，脯氨酸升高为常见的SZ内表型。研究已经记录了高碳水化血症的功能失调后果，例如异常谷氨酸能和多巴胺信号传导例如，导致认知缺陷和减弱的预脉冲抑制（PPI）。靶向高丙二元血症因此，DTNBP1模型可能会积极影响神经递质信号传导和恢复功能。这项拟议的研究旨在在以下特定目的下检验我们的假设。目标1：测试低维生素D和PODH和DTNBP1基因变体的相对分子贡献对Sz- 相关的高脱脂血症。在SZ患者和对照样品（n = 250）中，我们将测量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之间的牢固关系。来自我们的初步数据，我们预计80％的测得的高丙烯酸血症将来自低维生素-D，而 DTNBP1和PRODH变体将负责其余20％。因此，我们将执行分子对我们完整的研究队列（404名受试者），prodh筛选和DTNBP1变体的分析基因表达以及对变体关联的测试，以及与低维生素-D的相互作用脯氨酸抬高。 AIM 2：检查导致DTNBP1中高丙烯血症的分子途径模型。目标2a。分子分析将包括对PODH的外围和中枢神经系统组织表达的测定受调节的基因和COMT（PODH的下游）以及皮质，海马和外围脯氨酸水平。目标2B。利用SDY - / - 和PODH +/-鼠标的主神经元和星形胶质细胞，我们将直接通过用维生素D和硫代二酮药物胡椒酮（RZG）处理，上调PODH表达测试恢复PODH表达和降低的细胞脯氨酸。 AIM 3：靶向高脱脂血症在体内的DTNBP1模型中。我们将检查使用维生素D（AIM 3A），RZG（AIM 3B），并且，与车辆相比单独治疗，在体内恢复上述途径，并防止或减轻SDY - / - 缺陷例如，PPI和空间工作记忆。