L-type Calcium Channel SNP rs1006737: characterizing the genetic risks in MUD (Methamphetamine Use Disorder)

L 型钙通道 SNP rs1006737：表征 MUD（甲基苯丙胺使用障碍）的遗传风险

• 批准号: 10668210
• 负责人: Marilou A. Andres
• 金额: $ 21.83万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668210
• 关键词: Abstinence; Adopted; Age; Age Years; Alleles; Award; Basal Ganglia; Basic Science; Brain; Calcium; Calcium Channel; Cardiomyopathies; Cardiovascular Diseases; Cell Culture System; Cells; Central Nervous System; Cessation of life; Chronic; Cognition; Cognitive deficits; Cytosol; DNA Methylation; Data; Empirical Research; Encephalitis; Epigenetic Process; Exhibits; Functional disorder; Gender; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genotype; Glutamates; Goals; Heart; Human; Hypertension; Immune System Diseases; Impaired cognition; Individual; Inflammation; Inflammatory; Interleukin-6; Knowledge; L-Type Calcium Channels; Location; Magnetic Resonance Spectroscopy; Measures; Mental Depression; Mental disorders; Meta-Analysis; Methamphetamine; Methamphetamine dependence; Methamphetamine use disorder; Methamphetamine withdrawal; Methodology; Monitor; Moods; Myocardial dysfunction; N-acetylaspartate; Nerve Degeneration; Neurons; Neurotransmitters; Outcome; Paper; Participant; Pathologic; Patients; Physical activity; Physicians; Plasma; Play; Predisposition; Protons; Psychiatry; Psychoses; Recovery; Reporting; Research; Risk; Role; Scientist; Single Nucleotide Polymorphism; Sleep disturbances; Structure; Symptoms; TNF gene; Testing; Time; Tissues; Toxic effect; addiction; chemokine; clinical phenotype; comorbidity; craving; cytokine; depressive symptoms; effective therapy; gain of function; gain of function mutation; gamma-Aminobutyric Acid; genetic signature; genetic variant; heart rate variability; imaging science; improved outcome; individual patient; individualized medicine; inflammatory marker; interest; methamphetamine exposure; methamphetamine use; methamphetamine user; mobile application; myoinositol; neuroimaging; neuroinflammation; neuron loss; neuropsychiatric disorder; personalized medicine; psychostimulant; response; risk variant; sleep pattern; tool; white matter; wrist worn device

ABSTRACT Methamphetamine (METH) causes structural damage to the brain. This leads to serious cognitive dysfunction and other comorbid conditions (e.g., depression, cardiac dysfunction, etc.) that can persist even during abstinence, thus negatively impacting recovery. METH also induces immune dysfunction and injures neurons leading to neuronal death. However, it remains unclear whether brain inflammation plays a critical role during abstinence and whether continued inflammation contributes to persisting cognitive deficits. We also do not know whether genetic factors can regulate brain inflammation and response to METH exposure and withdrawal. Filling this gap in our knowledge is critical to developing effective treatment to improve outcomes for METH addicts. We found that long-term exposure to METH in a cell culture system resulted in increased expression of the L-type calcium (Ca2+) channel gene, leading to more Ca2+ entry into the cells. Too much Ca2+ in the cytosol is toxic to the cell. Genetic variants of the L-type Ca2+ channel gene, associated with a gain-of- function mutation and increased Ca2+ influx, have been implicated in various neuropsychiatric disorders like depression, which has been associated with cytokine/chemokine dysfunction. The release of specific pro- inflammatory markers is Ca2+-dependent. An increase of Ca2+ influx through L-type Ca2+ channels may drive more release of these cytokine/chemokine markers. Our long-term goal is to understand the mechanisms by which genetics underlie the changes in systemic and central nervous system (CNS) inflammation and how chronic inflammation may alter brain function and cognition during current METH use and abstinence. Our central hypothesis is that individuals with gain-of-function SNP s1006737 risk A/A genotype that promotes higher intracellular Ca2+ load will exhibit higher levels of pro-inflammatory markers in response to METH compared to METH-users without these risk alleles. Our Specific Aims are to 1) Compare brain gamma- aminobutyric acid (GABA), glutamate (Glu), myo-inositol (mI), and N-acetyl-aspartate (NAA) levels of Methamphetamine Use Disorder (MUD) subjects with the A/A and those with A/G (or G/G) genotypes and with non-MUD (A/A) subjects; and 2) Compare the plasma levels of pro-inflammatory markers of MUD subjects with different genotypes (A/A vs. A/G and G/G) and with non-MUD (A/A) subjects and determine epigenetic changes (i.e., DNA methylation levels). This Imaging-Science Track Award for Research Transition (I/START) application will allow the PI to adopt neuroimaging methodologies to test a hypothesis-driven by preliminary basic science findings.

抽象的 甲基苯丙胺（METH）会对大脑造成结构损害。这导致严重的认知功能障碍 以及其他合并症（例如，抑郁症，心脏功能障碍等），即使在 禁欲，从而对恢复产生负面影响。 METH还会诱导免疫功能障碍并损害神经元 导致神经元死亡。但是，尚不清楚脑部炎症在 戒酒以及持续炎症是否有助于持续的认知缺陷。我们也不 知道遗传因素是否可以调节脑部炎症和对甲基甲基甲基暴露的反应以及 提取。在我们的知识中填补这一空白对于开发有效的治疗以改善结果至关重要 对于冰毒成瘾者。我们发现，在细胞培养系统中长期暴露于METH导致增加 L型钙（Ca2+）通道基因的表达，导致Ca2+进入细胞的更多。 Ca2+太多 在细胞质中，对细胞有毒。 L型Ca2+通道基因的遗传变异，与获得 功能突变和CA2+涌入增加已与各种神经精神疾病有关 抑郁症，与细胞因子/趋化功能障碍有关。释放特定的pro- 炎症标记是Ca2+依赖性的。通过L型Ca2+通道增加Ca2+涌入可能会驱动 这些细胞因子/趋化因子标记物的更多释放。我们的长期目标是了解 哪种遗传学是全身和中枢神经系统（CNS）炎症的变化以及如何 慢性炎症可能会改变当前使用和戒酒期间的大脑功能和认知。我们的 中心假设是，具有功能获得SNP S1006737风险A/A基因型的人 较高的细胞内Ca2+负载将显示出较高水平的促炎标志物。 与没有这些风险等位基因的甲基动物使用者相比。我们的具体目的是1）比较脑γ- 氨基丁酸（GABA），谷氨酸（GLU），肌醇（MI）和N-乙酰基天冬氨酸（NAA）水平 A/A和具有A/G（或G/G）基因型的甲基苯丙胺使用障碍（MUD）受试者，并且 非穆德（a/a）受试者； 2）比较泥浆受试者的促炎标记的血浆水平 不同的基因型（A/A与A/G和G/G）和非MUD（A/A）受试者并确定表观遗传学 变化（即DNA甲基化水平）。这项成像科学轨道研究过渡奖（I/Start） 应用将使PI能够采用神经影像学方法来检验由初步驱动的假设驱动的 基础科学发现。