Vulnerability of DHCR7+/- mutation carriers to aripiprazole and trazodone treatment

DHCR7/-突变携带者对阿立哌唑和曲唑酮治疗的脆弱性

• 批准号: 9312958
• 负责人: Karoly Mirnics
• 金额: $ 49.75万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312958
• 关键词: 7-dehydrocholesterol; Antipsychotic Agents; Behavior; Behavioral; Biochemical; Biological Assay; Birth; Blood; Brain; Brain region; Cations; Cell Differentiation process; Cell Survival; Cell division; Cells; Cholesterol; Communication; Complex; Custom; Data; Dermal; Deterioration; Development; Developmental Disabilities; Emotions; Enzymes; Experimental Designs; Female; Fibroblasts; Frequencies; Gene Expression; Gene Expression Profiling; Gene Mutation; Genes; Genotype; Human; Inflammation; Injection of therapeutic agent; Investigation; Life; Measures; Modeling; Molecular Profiling; Monitor; Moods; Mothers; Motor; Mus; Mutant Strains Mice; Mutation; Names; Normal Cell; Nuclear Receptors; Oxidoreductase; Partner in relationship; Pathologic; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Posture; Preclinical Drug Evaluation; Review Literature; Severities; Smith-Lemli-Opitz Syndrome; Social Interaction; Symptoms; Testing; Therapeutic; Time; Toxic effect; Transcript; Transgenic Mice; Trazodone; Vulnerable Populations; aripiprazole; atypical antipsychotic; autism spectrum disorder; base; behavior test; cholesterol biosynthesis; cohort; design; experimental study; follow-up; inhibitor/antagonist; lipid biosynthesis; loss of function mutation; male; mouse model; mutant; mutation carrier; neurodevelopment; offspring; personalized medicine; postnatal; precision medicine; pregnant; response; sensory input

The last step in the cholesterol biosynthesis pathway is conversion of 7-dehydrocholesterol (7-DHC) to cholesterol, catalyzed by a single enzyme, 7-dehyrocholesterol reductase (DHCR7). To date, >150 DHCR7 loss-of-function mutations have been identified, with >1% heterozygous carriers in the human population. Heterozygous carriers have elevated 7-DHC levels. It has been well documented that 7-DHC is toxic, and its numerous spontaneous oxidative products (oxysterols) have disruptive effects on normal cell division and differentiation. 7-DHC levels can also markedly increase as a result of drug treatment. We recently performed a high throughput drug screening and found that aripiprazole (ARI- an atypical antipsychotic) and trazodone (TRZ - an antidepressant) both strongly increased 7-DHC levels. Further literature review revealed that ARI- and TRZ-treated patients have elevated 7-DHC levels, misclassifying some them as SLOS patients - even when they had two intact copies of the Dchr7 gene. In a follow-up experiments we observed that peripheral dermal fibroblasts from human DHCR7+/- mutation carriers also had elevated 7-DHC levels at baseline, which worsened as a result of ARI exposure. Our newest data indicate that ARI treatment of pregnant Dhcr7+/- mice have deleterious effects on the development of the offspring. Based on these data, we hypothesize that ARI/TRZ exposure and DHCR7+/- mutations potentiate each other, elevating 7-DHC levels into a pathological range. As a result, the spontaneous, toxic metabolites of 7-DHC will alter neural development and/or brain function, especially when DHCR7+/- mutation carrier mothers have DHCR7+/- offspring exposed to ARI or TRZ. We will test this central hypothesis in a patient-derived fibroblast model (Aim 1) and neurodevelopmental transgenic mouse models (Aims 2-3) at two different time points using a maternal genotype*offspring genotype*treatment paradigm. Aripiprazole, marketed under the name of Ablilify® is the most prescribed drug in the US, and the possibility that heterocyclic cationic amphiphile exposure might be deleterious to >1% of the human DHCR7+/- mutation carriers warrants further investigation. Developing personalized medicine approaches requires understanding Gene*Treatment interactions, and knowing the interaction between maternal genotype*offspring genotype*treatment is necessary to precisely define the population that is potentially vulnerable to ARI/TRZ exposure.

胆固醇生物合成途径的最后一步是将7-脱氢胆固醇（7-DHC）转化为 胆固醇，由单一酶，7-脱氢胆固醇还原酶（DHCR 7）催化。迄今为止，超过150个DHCR 7 已经鉴定了功能丧失突变，在人群中杂合携带者>1%。 杂合子携带者7-DHC水平升高。已充分证明7-DHC是有毒的，并且其 许多自发的氧化产物（氧化固醇）对正常细胞分裂具有破坏性作用， 分化7-DHC水平也可以显着增加作为药物治疗的结果。我们最近表演了 高通量药物筛选，发现阿立哌唑（ARI-非典型抗精神病药）和曲唑酮 (TRZ- 抗抑郁剂）都强烈增加7-DHC水平。进一步的文献回顾显示，ARI- TRZ治疗的患者7-DHC水平升高，将其中一些患者错误地归类为SLOS患者-甚至 当他们有两个完整的Dchr 7基因拷贝时。在后续的实验中，我们观察到， 来自人DHCR 7 +/-突变携带者的真皮成纤维细胞在基线时也具有升高的7-DHC水平， 由于ARI暴露而恶化。我们最新的数据表明ARI治疗怀孕的Dhcr 7 +/-小鼠， 对后代的发育有有害影响。根据这些数据，我们假设， ARI/TRZ暴露和DHCR 7 +/-突变相互增强，将7-DHC水平升高到 病理范围因此，7-DHC的自发有毒代谢产物将改变神经系统 发育和/或脑功能，特别是当DHCR 7 +/-突变携带者母亲具有DHCR 7 +/- 暴露于ARI或TRZ的后代。我们将在患者来源的成纤维细胞模型中检验这一中心假设 (Aim 1）和神经发育转基因小鼠模型（目的2-3）在两个不同的时间点， 母体基因型 * 后代基因型 * 治疗范例。阿立哌唑，以商品名Aripilify ® 是美国最常用的处方药，并且杂环阳离子两亲物暴露可能 对>1%的人DHCR 7 +/-突变携带者有害，需要进一步研究。发展中 个性化医疗方法需要了解基因 * 治疗的相互作用， 母体基因型 * 后代基因型 * 治疗之间的相互作用是必要的，以精确定义 可能易受ARI/TRZ暴露影响的人群。