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

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
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-06-01 至 2022-05-31

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中文摘要
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英文摘要
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.
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CORE B: Basic Neuroscience Services
  • 批准号:
    7758947
  • 项目类别:
  • 资助金额:
    $32.23万
  • 财政年份:
    2009
  • 负责人:
    Karoly Mirnics
  • 依托单位:
Neuroimmune Changes in Schizophrenia
  • 批准号:
    7570616
  • 项目类别:
  • 资助金额:
    $34.57万
  • 财政年份:
    2007
  • 负责人:
    Karoly Mirnics
  • 依托单位:
MOLECULAR PROFILE OF LAMINA-SPECIFIC ALTERATIONS IN THE DLPFC IN SCHIZOPHRENIA
Neuroimmune Changes in Schizophrenia
  • 批准号:
    7775052
  • 项目类别:
  • 资助金额:
    $34.44万
  • 财政年份:
    2007
  • 负责人:
    Karoly Mirnics
  • 依托单位:
海外基金