TRACKING NEURODEGENERATION IN EARLY WOLFRAM SYNDROME

追踪早期 Wolfram 综合征的神经退行性变

基本信息

  • 批准号:
    8380938
  • 负责人:
  • 金额:
    $ 53.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-17 至 2017-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Wolfram syndrome (WFS) is a rare (1 in 770,000) autosomal recessive genetic disease with clinical signs apparent in early childhood. It is characterized by insulin-dependent diabetes, followed by optic nerve atrophy, vision loss, hearing loss, diabetes insipidus and neurodegeneration, resulting in death in middle adulthood, typically due to brainstem atrophy-induced respiratory failure. There currently are no treatments that slow or stop this devastating deterioration. However, much is known about the mechanisms underlying these effects. The causative gene (WFS1) was identified by our group in 1998, and a number of loss-of-function mutations have been described. Cell and animal models have determined that WFS1 encodes an endoplasmic reticulum (ER) membrane-embedded protein called wolframin and that mutations lead to disturbances of ER calcium homeostasis, driving ER stress-mediated apoptosis. This process kills insulin producing pancreatic ¿-cells, leading to diabetes, and is thought to underlie the striking neurodegeneration in WFS. Work in animal models of WFS is progressing rapidly towards the identification of viable interventions for this process. Neurological features of the disease may be the most feasible to target and monitor in clinical trials, due to the fact that ¿-cell loss in the pancreas has already occurred by the time patient is diagnosed with WFS. Unfortunately, there is a dearth of information on the pattern of neurodegeneration associated with WFS, particularly in the early stages of the disease. Thus, the goal of the current proposal is to determine the pattern of early neurodegenerative changes in WFS. We will perform cross-sectional and longitudinal assessments of youth with WFS, targeting sensitive neural systems with quantified neuroimaging and behavioral measures. In addition, we will establish the utility of a WFS severity rating scale (WFS Unified Rating Scale or WURS). Preliminary data support the feasibility of this approach and its potential to generate important new information about neurodevelopmental and neurodegenerative patterns in WFS. This work is necessary to position the field for future clinical trials to test interventions for WS neurodegeneration. Ultimately, a better understanding of the trajectory of neurodegeneration in WFS and the development of effective interventions may be relevant to other more common neurodegenerative and endocrine (Type 1 and Type 2 diabetes) diseases in which ER stress has been implicated. PUBLIC HEALTH RELEVANCE: Wolfram syndrome is a rare genetic disease that affects young children, causing diabetes, vision and hearing loss and brain degeneration, resulting in death in mid-adulthood. There currently are no treatments that slow or stop this devastating deterioration. However, work in animal models of Wolfram syndrome is progressing rapidly towards the identification of viable interventions for this process. The goal of the current proposal is to determine the pattern of early neurodegenerative changes in Wolfram syndrome. This work is necessary to prepare for future clinical trials to test interventions for Wolfram syndrome neurodegeneration and may be relevant to other, more common disorders that share similar biological mechanisms.
描述(申请人提供):Wolfram综合征(WFS)是一种罕见的常染色体隐性遗传病(770,000人中有1例),临床症状在儿童早期明显。它的特点是胰岛素依赖型糖尿病,其次是视神经萎缩、视力丧失、听力丧失、尿崩症和神经变性,导致中年死亡,通常是由于脑干萎缩导致的呼吸衰竭。目前还没有治疗方法可以减缓或阻止这种毁灭性的恶化。然而,人们对这些效应背后的机制知之甚少。致病基因(WFS1)是我们小组在1998年发现的,并描述了一些功能丧失的突变。细胞和动物模型已经确定WFS1编码一种内质网(ER)膜嵌入蛋白wolframin,突变导致内质网钙稳态紊乱,推动内质网应激介导的细胞凋亡。这一过程杀死了产生胰岛素的胰腺细胞,导致糖尿病,并被认为是WFS显著神经变性的基础。WFS动物模型的工作正在迅速进展,以确定这一过程的可行干预措施。在临床试验中,这种疾病的神经学特征可能是最可行的靶向和监测,因为当患者被诊断为WFS时,胰腺中的细胞丢失已经发生。不幸的是,关于与WFS相关的神经退变模式的信息很少,特别是在疾病的早期阶段。因此,当前建议的目标是确定WFS的早期神经退行性变化的模式。我们将对患有WFS的年轻人进行横断面和纵向评估,通过量化的神经成像和行为测量瞄准敏感的神经系统。此外,我们还将建立WFS严重性评级表(WFS统一评级表或 WURS)。初步数据支持这种方法的可行性,以及它产生有关WFS神经发育和神经退行性变化模式的重要新信息的潜力。这项工作对于为未来的临床试验测试WS神经变性的干预措施定位领域是必要的。最终,更好地了解WFS中神经退行性变的轨迹和开发有效的干预措施可能与其他更常见的神经退行性疾病和内分泌疾病(1型和2型糖尿病)有关,内质网应激已被牵涉其中。 与公共卫生相关:Wolfram综合征是一种罕见的遗传性疾病,影响幼儿,导致糖尿病、视力和听力丧失以及大脑退化,导致中年死亡。目前还没有治疗方法可以减缓或阻止这种毁灭性的恶化。然而,Wolfram综合征动物模型的研究工作正在迅速进展,以确定这一过程的可行干预措施。目前这项提议的目标是确定Wolfram综合征早期神经退行性变化的模式。这项工作是为未来的临床试验做准备所必需的,以测试对Wolfram综合征神经变性的干预措施,并可能与具有类似生物学机制的其他更常见的疾病相关。

项目成果

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TAMARA G HERSHEY其他文献

TAMARA G HERSHEY的其他文献

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{{ truncateString('TAMARA G HERSHEY', 18)}}的其他基金

Plasma neurofilament light chain as a potential disease monitoring biomarker in Wolfram syndrome
血浆神经丝轻链作为 Wolfram 综合征潜在疾病监测生物标志物
  • 批准号:
    10727328
  • 财政年份:
    2023
  • 资助金额:
    $ 53.65万
  • 项目类别:
Tracking Neurodegeneration in Early Wolfram Syndrome
追踪早期 Wolfram 综合征的神经退行性变
  • 批准号:
    10452695
  • 财政年份:
    2012
  • 资助金额:
    $ 53.65万
  • 项目类别:
TRACKING NEURODEGENERATION IN EARLY WOLFRAM SYNDROME
追踪早期 Wolfram 综合征的神经退行性变
  • 批准号:
    8657470
  • 财政年份:
    2012
  • 资助金额:
    $ 53.65万
  • 项目类别:
Tracking Neurodegeneration in Early Wolfram Syndrome
追踪早期 Wolfram 综合征的神经退行性变
  • 批准号:
    10248363
  • 财政年份:
    2012
  • 资助金额:
    $ 53.65万
  • 项目类别:
Tracking Neurodegeneration in Early Wolfram Syndrome
追踪早期 Wolfram 综合征的神经退行性变
  • 批准号:
    9762126
  • 财政年份:
    2012
  • 资助金额:
    $ 53.65万
  • 项目类别:
TRACKING NEURODEGENERATION IN EARLY WOLFRAM SYNDROME
追踪早期 Wolfram 综合征的神经退行性变
  • 批准号:
    8532946
  • 财政年份:
    2012
  • 资助金额:
    $ 53.65万
  • 项目类别:
Tracking Neurodegeneration in Early Wolfram Syndrome
追踪早期 Wolfram 综合征的神经退行性变
  • 批准号:
    9974547
  • 财政年份:
    2012
  • 资助金额:
    $ 53.65万
  • 项目类别:
TRACKING NEURODEGENERATION IN EARLY WOLFRAM SYNDROME
追踪早期 Wolfram 综合征的神经退行性变
  • 批准号:
    9045660
  • 财政年份:
    2012
  • 资助金额:
    $ 53.65万
  • 项目类别:
CENTRAL DOPAMINE RECEPTORS IN OBESITY
肥胖中枢多巴胺受体
  • 批准号:
    8050090
  • 财政年份:
    2010
  • 资助金额:
    $ 53.65万
  • 项目类别:
CENTRAL DOPAMINE RECEPTORS IN OBESITY
肥胖中枢多巴胺受体
  • 批准号:
    7789337
  • 财政年份:
    2010
  • 资助金额:
    $ 53.65万
  • 项目类别:

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