Biosignatures Classifying Binge Alcohol-Induced Bone Damage and Drug Intervention

描述（由申请人提供）：酗酒在青少年和成年人中都很普遍，但人们对酗酒及其相关的高血液酒精含量对骨骼健康的影响知之甚少。我们的长期目标是通过识别检测暴饮酒精引起的骨质流失的基因特征模式，以及用治疗药物减轻骨损伤，来表征暴饮酒精对青少年、成人和骨质减少的骨骼的破坏性影响。我们的假设是：1。酗酒会导致骨骼损伤，这种损伤可以通过一种独特的基因特征谱在早期阶段检测到。2. 通过靶向抗骨吸收治疗预防狂饮酒精引起的骨损伤，可调节这些骨特异性狂饮酒精调节基因子集的表达，从而产生反映狂饮酒精对骨吸收影响的新特征谱。我们基于以下初步数据提出了这些假设：1)鉴定了成年雄性大鼠在酗酒模式下的骨骼中独特的基因表达谱；2)通过同时进行抗吸收治疗来调节酒精调节基因的亚群。基于这些观察结果，我们的实验重点是在青春期、成年和骨质减少的成年大鼠中识别早期酗酒引起的骨损伤的基因特征。酒精引起的骨质流失的基因特征特征和治疗干预将允许早期发现骨损伤，并提供允许识别新疗法的信息，从而导致对酒精滥用和其他原因导致的骨质流失进行合理、有针对性的治疗。

DESCRIPTION (provided by applicant): Binge drinking of alcoholic beverages is prevalent among both adolescents and adults, but little is known about the effects that binge drinking with its associated high blood alcohol levels has on skeletal health. Our long-term goal is to characterize the damaging effects of binge alcohol on the adolescent, adult and osteopenic adult skeleton by identifying gene signature patterns that detect binge alcohol-induced bone loss and attenuation of bone damage with therapeutic agents. Our hypotheses are: 1. Binge alcohol exposure causes bone damage that is detectable in its early stages by a unique gene signature profile. 2. Prevention of binge alcohol-induced bone damage with targeted anti-resorptive therapy modulates the expression of a subset of these bone-specific binge alcohol-regulated genes, producing a novel signature profile reflective of the effect of binge alcohol on bone resorption. We base these hypotheses on preliminary data showing: 1) Identification of unique gene expression profiles in bone from adult male rats given alcohol in a binge-like pattern and, 2) Modulation of a subset of alcohol-regulated genes by concurrent anti-resorptive therapy. Based on these observations, our experimental focus is on the identification of gene signatures that detect early binge alcohol-induced bone damage in adolescent, adult and osteopenic adult rats. Gene signatures characteristic of alcohol-induced bone loss and therapeutic intervention will allow early detection of bone damage and provide information allowing identification of novel therapeutics, leading to rational, targeted treatment of bone loss due to alcohol abuse and other causes. The specific aims of this proposal are to: 1. Identify binge alcohol-induced, bone damage-related gene signatures in adolescent rats. We will identify bone-specific signature patterns that detect the damage caused by binge alcohol to bone (decreased bone density and compressive strength) in male and female adolescent rats. 2. Characterize gene signatures in binge alcohol damaged and therapy-protected adult rat bone. Binge alcohol-related bone-specific signatures may differ with developmental stage, thus we will use adult male and female rats to identify new bone signature patterns related to both binge alcohol-specific bone damage and modulation of signature patterns with anti-resorptive (osteoprotegerin) therapy in adult animals. 3. Compare gene signature profiles of binge alcohol-induced and ovariectomy-induced bone damage. We will identify bone-specific signatures in ovariectomized (OVX) rats with and without binge alcohol treatment, allowing us to define similarities and differences in the molecular pathways leading to pathologic bone loss caused by the distinct, additive bone damaging insults of binge alcohol exposure and estrogen deficiency.