RXR Alpha: Screening a Candidate for Late Life Disease

RXR Alpha：筛选晚年疾病候选人

• 批准号: 6479623
• 负责人: Brock Allen Beamer
• 金额: $ 8.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479623
• 关键词: aging; body composition; bone density; bone imaging /visualization /scanning; disease /disorder onset; gene mutation; genetic polymorphism; genetic regulation; genetic screening; genotype; human old age (65+); human subject; medical records; muscle strength; nuclear receptors; osteoporosis; patient oriented research; phenotype; physical fitness; questionnaires; skin

While changes in body composition-and often disastrous sequelae thereof-universally accompany old age, there is tremendous variability in their onset, pattern and severity. The long term objective of this project is to better understand the molecular basis for this heterogeneity, and thereby the pathways which underlie such changes. The immediate focus is whether some variability is due to genetic heterogeneity in the nuclear receptor RXRalpha (9-cis retinoic acid receptor). RXRalpha is essential for the action of many nuclear receptors (e.g. PPAR, THR, RAR) and lays significant roles in development and maintenance of bone, muscle and skin tissue (among other tissues). Ligand and artificial mutation suggest that alterations in RXRalpha activity or interactivity could have a variety of phenotypic consequences. We hypothesize that mutations in genes such as RXRalpha could contribute to (or protect against) severe or early onset declines in bone, muscle or skin. Specific aim #1 is to recruit small cohorts of well-characterized older individuals free of confounding conditions (e.g. glucocorticoid use) selected for severe and/or early onset: (i) osteoporosis, (ii) muscle weakness, (iii) decreased skin integrity, or (iv) absence of these at extreme old age. Specific Aim #2 is to perform SSCP analysis of RXRalpha on genomic DNA from 15 individuals of each cohort, and begin characterization of any variants identified. Beyond the scope of this pilot project is (i) screening these cohorts for variation in other genes that may influence musculoskeletal or dermatologic changes with age; (ii) performing functional analyses of large definitive association studies with any variants found from this screen; or (iii) assessing other conditions potentially influenced by variation in RXRalpha (e.g. thyroid function, vision). However, this project should form bases from which such questions could be explored. Within its scope, it may help to elucidate general pathways underlying age-related changes in body composition/function, which ultimately will lead to improved means of preventing and treating their sequelae (perhaps with the RXRalpha agonists/antagonists now being developed).

虽然身体成分的变化——常常是灾难性的后遗症——普遍伴随着老年，但它们的发生、模式和严重程度却有很大的差异。该项目的长期目标是更好地了解这种异质性的分子基础，从而了解这种变化背后的途径。当前关注的焦点是，某些变异是否由于核受体rxrα（9-顺式维甲酸受体）的遗传异质性。rxrα对许多核受体（如PPAR、THR、RAR）的作用至关重要，并在骨骼、肌肉和皮肤组织（以及其他组织）的发育和维持中发挥重要作用。配体和人工突变表明，rxrα活性或相互作用的改变可能会产生各种表型后果。我们假设，RXRalpha等基因的突变可能会导致（或防止）骨骼、肌肉或皮肤的严重或早期衰退。具体目标#1是招募没有混杂条件（如使用糖皮质激素）的特征良好的老年人小队列，选择严重和/或早期发病：(1)骨质疏松症，(2)肌肉无力，(3)皮肤完整性下降，或(4)极端老年缺乏这些。具体目标#2是对每个队列中15个个体的基因组DNA进行RXRalpha的SSCP分析，并开始对所识别的任何变体进行表征。超出本试点项目范围的是(i)筛选这些队列中可能影响肌肉骨骼或皮肤变化的其他基因的变异；（ii）对从该筛选中发现的任何变异进行大型明确关联研究的功能分析；或（iii）评估其他可能受RXRalpha变异影响的情况（如甲状腺功能、视力）。然而，这个项目应该成为探索这些问题的基础。在其范围内，它可能有助于阐明与年龄相关的身体成分/功能变化的一般途径，最终将导致预防和治疗其后遗症的改进方法（可能是目前正在开发的RXRalpha激动剂/拮抗剂）。