RXR Alpha: Screening a Candidate for Late Life Disease

虽然身体组成的变化--以及由此产生的灾难性后遗症--普遍伴随着老年，但它们的发生、模式和严重程度存在巨大的差异。该项目的长期目标是更好地了解这种异质性的分子基础，从而了解这种变化的基础途径。目前的焦点是是否有些变异是由于遗传异质性的核受体RXR α（9-顺式视黄酸受体）。RXR α是许多核受体（例如，PPAR，THR，RAR）的作用所必需的，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RXR α活性或相互作用的改变可能具有多种表型后果。我们假设RXR α等基因的突变可能导致（或防止）骨骼、肌肉或皮肤的严重或早发性衰退。具体目标#1是招募特征良好的老年个体的小队列，这些老年个体没有选择的严重和/或早发性的混杂疾病（例如，糖皮质激素使用）：（i）骨质疏松症，（ii）肌无力，（iii）皮肤完整性降低，或（iv）在极端老年时不存在这些疾病。具体目标#2是对来自每个队列的15个个体的基因组DNA进行RXR α的SSCP分析，并开始表征鉴定的任何变体。超出该试点项目的范围是（i）筛选这些队列中可能影响肌肉骨骼或皮肤随年龄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）评估可能受RXR α变异影响的其他条件（例如甲状腺功能，视力）。然而，这一项目应成为探讨这些问题的基础。在其范围内，它可能有助于阐明身体组成/功能中与年龄相关的变化的一般途径，这最终将导致预防和治疗其后遗症的改进方法（可能与现在正在开发的RXR α激动剂/拮抗剂）。

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).