Human Uremic Persistent Hyperparathyroidism: Functional and Molecular Aspects

描述（由申请人提供）： 因终末期肾衰竭接受透析的患者通常会出现甲状旁腺过度活动，这可能在成功的肾移植后持续很长时间，并导致移植物和受体的不良结局。移植后甲状旁腺功能异常、抑制不良的原因研究很少，也不完全清楚。移植后持续性继发性甲状旁腺功能亢进（PSHPT）的患者预期会显示甲状旁腺细胞（PTC）功能的改变，这是由于蛋白质/基因表达和/或影响增殖、PTH基因表达和分泌设定点的功能的变化。患有常染色体显性遗传性多囊肾病（ADPKD）的移植受者接受移植后甲状旁腺切除术的风险较高。PTC中多囊蛋白（PC）的鉴定及其作为质膜钙传感器/通道的功能已得到很好的描述。PC还利用与钙敏感受体（CaR）类似的细胞内信号传导途径。这些观察结果支持PCL在甲状旁腺功能中发挥作用的假设。阐明PSHPT的分子基础和PCL在PTC功能中的作用将有助于开发可以优化患者和移植物结局的治疗和策略。这些问题将通过以下具体目标来解决：目标1：通过定量甲状旁腺分泌和增殖对细胞外钙浓度（Ca 2+）和1，25（OH）2维生素D3变化的体外反应，阐明肾移植患者相对于透析患者PSHPT持续高分泌和增殖的特征。目标二：研究有或无ADPKD和PSHPT的移植和透析患者的甲状旁腺在CaR调节的信号通路方面的关键定性和定量差异，这些信号通路与原发性HPT和透析患者中异常Ca 2+调节的PTH释放有关。具体目标3：确定异常Ca 2+调节过程与有无PKD的透析和移植患者PTC中控制甲状旁腺功能的关键基因表达之间的关系。如果这些基因过度表达或表达不足，我们将评估使用腺相关病毒载体或RNA沉默纠正其表达的效果。具体目标4：使用DNA微阵列鉴定导致PSHPT的新基因。

DESCRIPTION (provided by applicant): Patients receiving dialysis for end stage kidney failure often develop overactivity of their parathyroid glands, which can persist long after successful kidney transplantation and contributes to adverse graft and recipient outcomes. Causes of the abnormal, poorly suppressible parathyroid function after transplantation have been little studied and are incompletely understood. Patients with post-transplant, persistent secondary hyperparathyroidism (PSHPT) would be expected to show alterations in parathyroid cell (PTC) function due to changes in protein/gene expression and/or function influencing proliferation, PTH gene expression and set-point of secretion. Transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) are at higher risk for post transplant parathyroidectomy. The identification of polycystins (PC) in PTC's, and their function as plasma membrane calcium sensors/channels have been well described. PC's also utilize intracellular signaling pathways similar to those of the calcium-sensing receptor (CaR). These observations support the hypothesis that PCL's play a role in parathyroid function. Elucidating the molecular basis of PSHPT and the role of PCL's in PTC function will assist in developing therapies and strategies that could optimize patient and graft outcomes. These issues will be addressed by undertaking the following specific aims: Aim 1: Elucidate the characteristics of persistent hypersecretion and proliferation characteristic of PSHPT in renal transplant patients relative to dialysis patients, by quantifying the parathyroid secretory and proliferative responses in vitro to changes in the extracellular calcium concentration (Ca2+) and 1,25 (OH)2 vitamin D3. Aim 2: Investigate the key qualitative and quantitative differences between parathyroid glands of transplant and dialysis patients with or without ADPKD and PSHPT with regard to CaR-regulated signaling pathways that have been implicated in the abnormal Ca2+-regulated PTH release in primary HPT and dialysis patients. Specific Aim 3: Determine the relationship between abnormal Ca2+-regulated processes and the expression of key genes implicated in the control of parathyroid function in PTC's of dialysis and transplant patients with and without PKD. If these genes are over- or underexpressed, we will assess the effect of correcting their expression using adeno-associated viral vectors or RNA silencing. Specific Aim 4: Identify novel genes contributing to PSHPT using DNA microarrays.