PATHOGENESIS AND PATHOPHYSIOLOGY OF FAMILIAL NEUROHYPOPHYSEAL DIABETES

家族性神经垂体糖尿病的发病机制和病理生理学

• 批准号: 6304172
• 负责人: GARY L. ROBERTSON
• 金额: $ 2.05万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6304172
• 关键词: clinical research; cytotoxicity; disease /disorder etiology; family genetics; gene mutation; human subject; molecular pathology; nephrogenic diabetes insipidus; neurons; pathologic process

The objective of this study is to obtain additional clinical and molecular genetic data to test the hypothesis that familial neurohypophyseal diabetes insipidus (FNDI) is due to mutations in the coding region of the vasopressin-neurophysin II gene that directs the production of a mutant preprohormone that accumulates in and destroys magnocellular neurons because it can not be folded and processed efficiently. The studies will be performed in all consenting affected and unaffected members of at least 14 American kindreds in which FNDI is known or presumed to be segregating. The subjects will be admitted to the Clinical Research Center at 1 to 5 year intervals for measurements of fluid intake and urine output, plasma electrolytes, plasma and urinary vasopressin, urine aquaporin II and abnormal forms of "big vasopressin" under basal conditions and during a fluid deprivation/hypertonic saline infusion or water load/hypertonic saline infusion test. Subjects will also undergo MRI of the pituitary-hypothalamic area and have blood collected for sequencing of the vasopressin-neurophysin gene. Affected subjects will undergo a therapeutic trial of desmopressin (DDAVP). A few subjects who undergo spontaneous remissions of their diabetes insipidus may also receive short infusions of oxytocin or vasopressin antagonists to determine if urinary dilution occurs.

本研究的目的是获得更多的临床和分子遗传学数据，以检验以下假设：家族性神经垂体尿崩症 (FNDI) 是由于加压素-神经素 II 基因编码区的突变所致，该基因指导突变前激素原的产生，该突变前激素原在大细胞神经元中积聚并被破坏，因为它无法有效折叠和加工。 这些研究将在至少 14 个美国亲属的所有同意的受影响和未受影响的成员中进行，其中 FNDI 已知或推测在这些亲属中进行了隔离。 受试者将每隔 1 至 5 年进入临床研究中心，在基础条件下和液体剥夺/高渗盐水输注或水负荷/高渗盐水输注测试期间测量液体摄入量和尿量、血浆电解质、血浆和尿液加压素、尿液水通道蛋白 II 和异常形式的“大加压素”。 受试者还将接受垂体-下丘脑区域的 MRI 扫描，并收集血液用于加压素-神经素基因测序。 受影响的受试者将接受去氨加压素 (DDAVP) 的治疗试验。 一些尿崩症自发缓解的受试者也可能接受短时间输注催产素或加压素拮抗剂以确定是否发生尿液稀释。