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

维生素-D-PRODH-

基本信息

批准号：
8775262
负责人：
CATHERINE L CLELLAND
金额：
$ 43.85万
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/8775262
关键词：
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 Health 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 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 cognitive performance 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 response restoration rosiglitazone screening

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：精神分裂症（SZ）的最高遗传风险是由染色体22q11的半合理微骨骼赋予的。脯氨酸脱氢酶基因（PODH）位于公共缺失区域，并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突变或包含PODH的CNV引起的周围性高蛋白质血症与认知障碍和iQ降低有关。我们最近报道了高丙二元血症与SZ的高度显着关联。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。我们的发现表明，通过丧失PODH表达，由维生素-D和DTNBP1调节的生物学途径的收敛性，脯氨酸升高为常见的SZ内表型。研究已经记录了高碳酸氢血症的功能失调后果，例如异常的谷氨酸能和多巴胺信号传导，导致认知缺陷和减弱的预硫化抑制（PPI）。因此，靶向DTNBP1模型中的高丙烯酸血症可能会对神经递质信号传导和恢复功能产生积极影响。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，PODH和DTNBP1基因变异的相对分子贡献，对SZ-相关的高丙烯酸血症。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，从而证实脯氨酸升高和低维生素-D之间的牢固关系。从我们的初步数据中，我们预计80％的测得的高碳水化血症将来自低维生素-D，而DTNBP1和PODH变体将负责其余20％。因此，我们将对我们的完整研究队列（404名受试者），PODH的筛选和DTNBP1变体进行分子分析，这些变体改变了基因表达，并测试了变体关联的测试，以及与硫酸硫酸盐升高的结果相互作用。 AIM 2：检查导致DTNBP1模型中高原血症的分子途径。目标2a。分子分析将包括PODH，p53调控基因和COMT（PODH的下游）的外围和中枢神经系统组织表达的测定，以及皮质，海马和外围脯氨酸水平。目标2B。利用来自SDY - / - 和PODH +/-小鼠的原发性神经元和星形胶质细胞，我们将通过维生素D和噻唑烷二酮药物胡萝卜素（RZG）直接上调PODH表达，测试以恢复PODH表达并减少细胞脯氨酸。 AIM 3：靶向体内DTNBP1模型中的高脂血症。我们将检查维生素D（AIM 3A），RZG（AIM 3B）的治疗是否是否与仅驾驶饮食（AIM 3C）相比，与仅使用媒介物治疗相比，寻求降低脱靶效应的影响（AIM 3C）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。