Genetic Factors of Bone Loss in Older Adults Taking Antidepressants

六分之一的老年人服用抗抑郁药，通常是血清素再摄取抑制剂（SRI）， 百忧解和左洛复临床前和流行病学研究均表明SRI加速 骨质流失是一个主要的公共健康问题，因为骨质疏松症给人类和经济带来了巨大负担。 尽管具有公共卫生意义，但SRI与骨丢失加速之间的关系 仍然知之甚少，未经证实。5-羟色胺是许多组织中重要的信号分子 包括血小板肠和骨头这个，再加上被标记的 SRI的神经递质效应，表明SRI可能引起非神经细胞中细胞信号传导的变化。 导致骨流失加速。我们的初步数据表明，遗传变异可能 导致SRI介导的骨丢失的易感性，在此，我们提出了一项明确的研究， SRI用于解决这一问题。我们利用一个大的，正在进行的随机 对照试验测试抗抑郁治疗策略在老年人。该试验提供了 一个理想的父母试验，以测试SRI暴露对骨骼健康的长期影响，并确定 常见和罕见的遗传变异，改变SRI介导的骨丢失的风险。然后我们将 使用基于CRISPRi的筛选快速验证候选基因和变体的功能影响 在细胞中。该项目利用了正在进行的大规模抗抑郁药临床试验， 新的分子技术来证明SRI介导的骨丢失及其遗传效应 修饰语它将阐明SRI是否、为什么以及在哪些人中导致骨质疏松症，改善患者 老年人的护理和健康结果，并确定骨骼健康的新治疗目标。

One in six older adults takes an antidepressant, usually serotonin reuptake inhibitors (SRIs) such as Prozac and Zoloft. Both preclinical and epidemiological studies suggest that SRIs accelerate bone loss, a major public health concern given the high human and economic burden of osteoporosis. Despite the public health significance, the relationship between SRIs and accelerated bone loss remains poorly understood and unproven. Serotonin is a prominent signaling molecule in many tissues outside of the brain including platelets, intestines, and bone. This, combined with the marked serotonergic effects of SRIs, suggests SRIs might elicit changes in cell signaling in non-neural tissues leading to accelerated bone loss. Our preliminary data suggest that genetic variation may contribute to susceptibility to SRI-mediated bone loss, and herein we propose a definitive study of bone turnover with SRI use to address this. We take advantage of a large, ongoing randomized controlled trial testing antidepressant treatment strategies in older adults. This trial provides an ideal parent trial to test the long-term effects of SRI exposure on bone health and to identify both common and rare genetic variants that modify risk for SRI-mediated bone loss. We will then rapidly validate the functional impact of candidate genes and variants using a CRISPRi-based screen in cells. This project leverages both an ongoing large-scale clinical trial of antidepressants and novel molecular techniques to demonstrate the effects of SRI-mediated bone loss and their genetic modifiers. It will clarify whether, why, and in whom SRIs lead to osteoporosis, improve patient care and health outcomes for older adults, and identify novel treatment targets for bone health.