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

摘要 甲基苯丙胺（METH）会对大脑造成结构性损伤。这会导致严重的认知功能障碍 和其它共病状况（例如，抑郁症、心功能障碍等）即使在 禁欲，从而对康复产生负面影响。METH还诱导免疫功能障碍和损伤神经元 导致神经元死亡。然而，目前尚不清楚脑炎症是否在脑损伤中起关键作用。 禁欲以及持续的炎症是否会导致持续的认知缺陷。我们也不 知道遗传因素是否可以调节大脑炎症和对METH暴露的反应， 戒断填补我们知识中的这一空白对于开发有效治疗以改善结果至关重要 为冰毒成瘾者。我们发现，在细胞培养系统中长期暴露于METH会导致细胞凋亡增加。 L-型钙（Ca 2+）通道基因的表达，导致更多的Ca 2+进入细胞。Ca 2+过多 对细胞有毒。L型钙通道基因的遗传变异，与获得性钙通道相关。 功能突变和Ca 2+内流增加，与各种神经精神疾病有关， 抑郁症，这与细胞因子/趋化因子功能障碍有关。释放特定的亲- 炎症标志物是Ca 2+依赖性的。通过L-型Ca 2+通道的Ca 2+内流的增加可以驱动 这些细胞因子/趋化因子标志物的更多释放。我们的长期目标是通过 系统性和中枢神经系统（CNS）炎症变化的遗传学基础以及如何 慢性炎症可能会改变脑功能和认知在当前METH使用和禁欲。我们 中心假设是，具有功能获得性SNP s1006737风险A/A基因型的个体， 细胞内Ca 2+负荷越高，对METH的反应中促炎标志物的水平越高 与没有这些风险等位基因的甲基苯丙胺使用者相比。我们的具体目标是1）比较大脑伽马- 氨基丁酸（GABA）、谷氨酸（Glu）、肌醇（mI）和N-乙酰天冬氨酸（NAA）水平。 甲基苯丙胺使用障碍（MUD）受试者与A/A和那些与A/G（或G/G）基因型和 非MUD（A/A）受试者;和2）将MUD受试者的促炎标志物的血浆水平与非MUD（A/A）受试者的促炎标志物的血浆水平进行比较。 不同基因型（A/A vs. A/G和G/G）和非MUD（A/A）受试者，并确定表观遗传 改变（即，DNA甲基化水平）。这个成像科学跟踪奖的研究过渡（I/START） 应用程序将允许PI采用神经影像学方法来测试由初步 基础科学发现

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.