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: 7408566
• 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/7408566
• 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）：青少年和成年人都普遍存在酒精饮料的暴饮暴食，但对与其相关的高血醇水平暴饮暴食对骨骼健康的饮酒的影响知之甚少。我们的长期目标是通过鉴定检测出检测暴饮暴食诱发的骨质流失以及对治疗剂的骨骼损伤的基因签名模式来表征暴饮暴食对青少年，成人和骨质减少成人骨骼的破坏性影响。我们的假设是：1。暴饮暴食会导致骨损伤，通过独特的基因签名特征在早期阶段可检测到骨骼损伤。 2。防止酒精诱导的骨骼损伤使用靶向抗敏感性治疗调节这些骨特异性暴饮暴食基因的一部分的表达，从而产生了一种新颖的特征，反映了暴饮暴食对骨吸收的影响。我们将这些假设以初步数据为基础：1）鉴定出以暴饮暴食方式给予酒精的成年雄性大鼠骨骼中的独特基因表达谱，以及2）通过并发抗敏感性疗法调节酒精调节基因的子集。基于这些观察结果，我们的实验重点是鉴定基因特征，这些基因特征检测到青少年，成人和骨质减少成年大鼠的早期暴饮暴食引起的骨损伤。酒精引起的骨质流失和治疗性干预的基因特征将允许尽早发现骨骼损伤，并提供信息以鉴定新的治疗剂，从而导致合理的，有针对性的因酒精滥用和其他原因而导致的骨质流失。 该提案的具体目的是：1。识别青少年大鼠中与酒精诱导的，与骨损伤相关的基因的特征。我们将确定骨骼特异性的特异性特异性特异性特异性特异性特异性特异性特异性特异性特异性签名模式，这些模式在男性和雌性青少年大鼠中因暴饮暴食到骨骼（骨密度降低和抗压强度）而造成的损害。 2。表征在暴饮暴食中特征的基因特征和受治疗保护的成年大鼠骨的特征。暴饮暴食相关的骨特异性特异性特异性可能会随发育阶段的不同而有所不同，因此我们将使用成年男性和雌性大鼠识别与抗毒剂特异性骨损伤以及对成年动物中抗敏感性（骨蛋白酶）治疗的签名模式相关的新骨骼签名模式。 3。比较暴饮精酒诱导的和卵巢切除术引起的骨损伤的基因特征。 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.