Biosignatures Classifying Binge Alcohol-Induced Bone Damage and Drug Intervention

对酗酒引起的骨损伤进行分类的生物特征和药物干预

• 批准号: 7232111
• 负责人: JOHN J. CALLACI
• 金额: $ 23.07万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7232111
• 关键词: Acute; Adolescent; Adult; Age-Related Bone Loss; Alcohol abuse; Alcohol consumption; Alcoholic Beverages; Alcohols; Animals; Arts; Behavior; Biological; Biological Markers; Biomechanics; Blood alcohol level measurement; Bone Density; Bone Resorption; Bone Tissue; Cells; Characteristics; Chronic; Combined Modality Therapy; Compressive Strength; Computer software; Computers; Condition; Custom; Data; Detection; Development; Diagnostic; Disease; Early Diagnosis; Elderly; Estrogens; Failure; Female; Female Adolescents; Fracture; Future; Gene Expression; Gene Expression Profile; Genes; Goals; Harvest; Health; Histocompatibility Testing; Hormones; Individual; Intervention; Laboratories; Maintenance; Male Adolescents; Measures; Medical; Menopause; Modeling; Molecular; Molecular Profiling; Monitor; Osteoporosis; Ovariectomy; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pilot Projects; Population; Population Heterogeneity; Postmenopause; Prevention; Principal Investigator; Process; Rattus; Reproducibility; Research Personnel; Risedronate; Risk; Risk Factors; Sampling; Screening procedure; Skeletal system; Skeleton; Staging; Symptoms; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Treatment Efficacy; Tumor necrosis factor receptor 11b; Validation; Week; alcohol abuse therapy; alcohol effect; alcohol exposure; attenuation; base; binge drinking; bone; bone health; bone loss; density; design; lifestyle intervention; male; mature animal; non-alcoholic; novel; novel therapeutics; prevent; problem drinker; programs; response; spine bone structure; tomography

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.

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基因特征模式来表征酗酒对青少年、成人和骨质疏松的成人骨骼的破坏性影响，这些基因特征模式可检测酗酒引起的骨质流失和治疗药物对骨损伤的减弱。我们的假设是： 1. 酗酒会导致骨损伤，这种损伤可以通过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来预防酗酒引起的骨损伤，调节这些骨特异性酗酒调节基因的子集的表达，产生反映酗酒对骨吸收影响的新特征谱。我们基于这些假设的初步数据显示：1）鉴定出以暴饮模式饮酒的成年雄性大鼠骨骼中独特的基因表达谱，2）通过同时的抗吸收疗法调节酒精调节基因的子集。基于这些观察，我们的实验重点是鉴定基因特征，以检测青少年、成年和骨质疏松成年大鼠的早期酗酒引起的骨损伤。酒精引起的骨质流失的基因特征和治疗干预将有助于及早发现骨损伤，并提供识别新疗法的信息，从而对酗酒和其他原因造成的骨质流失进行合理、有针对性的治疗。 该提案的具体目标是： 1. 鉴定青春期大鼠中酗酒引起的骨损伤相关基因特征。我们将确定骨骼特异性特征模式，以检测雄性和雌性青春期大鼠酗酒对骨骼造成的损害（骨密度和抗压强度降低）。 2. 表征酗酒损伤和治疗保护的成年大鼠骨骼中的基因特征。酗酒相关的骨特异性特征可能因发育阶段而异，因此我们将使用成年雄性和雌性大鼠来识别与酗酒特异性骨损伤相关的新骨特征模式，以及成年动物中通过抗吸收（骨保护素）疗法调节特征模式。 3. 比较酗酒引起的和卵巢切除引起的骨损伤的基因特征谱。我们将鉴定接受和不接受酗酒治疗的卵巢切除（OVX）大鼠的骨特异性特征，从而使我们能够定义导致病理性骨质流失的分子途径的相似性和差异，这些病理性骨质流失是由酗酒暴露和雌激素缺乏造成的独特的、附加的骨损伤性损伤引起的。