TRACKING NEURODEGENERATION IN EARLY WOLFRAM SYNDROME

描述（由申请人提供）：Wolfram综合征（WFS）是一种罕见的（1/770，000）常染色体隐性遗传疾病，在儿童早期具有明显的临床体征。其特征是胰岛素依赖性糖尿病，随后是视神经萎缩、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引起的呼吸衰竭。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，对这些影响的机制了解很多。致病基因（WFS 1）是由我们的小组在1998年确定的，并已描述了一些功能丧失的突变。细胞和动物模型已经确定，WFS 1编码一种名为钨蛋白的内质网（ER）膜包埋蛋白，突变导致ER钙稳态紊乱，驱动ER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中惊人的神经变性的基础。WFS动物模型的工作正在迅速取得进展，以确定这一过程的可行干预措施。该疾病的神经学特征可能是临床试验中最可行的目标和监测，因为在患者被诊断患有WFS时，胰腺中的细胞损失已经发生。不幸的是，缺乏与WFS相关的神经变性模式的信息，特别是在疾病的早期阶段。因此，目前建议的目标是确定WFS早期神经退行性变化的模式。我们将对患有WFS的青少年进行横断面和纵向评估，通过量化的神经成像和行为测量来针对敏感的神经系统。此外，我们将建立WFS严重性评级量表（WFS统一评级量表或 WURS）。初步的数据支持这种方法的可行性和它的潜力，以产生重要的新信息的神经发育和神经退行性疾病的模式在WFS。这项工作是必要的，以定位未来的临床试验领域，以测试WS神经变性的干预措施。最终，更好地了解WFS中神经变性的轨迹和有效干预措施的发展可能与其他更常见的神经变性和内分泌（1型和2型糖尿病）疾病有关，其中ER应激已被牵连。 公共卫生相关性：Wolfram综合征是一种罕见的遗传性疾病，影响幼儿，导致糖尿病，视力和听力损失以及大脑退化，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综合征动物模型的工作正在迅速取得进展，以确定这一过程的可行干预措施。本研究的目的是确定Wolfram综合征早期神经退行性改变的模式。这项工作是必要的，为未来的临床试验做准备，以测试Wolfram综合征神经退行性变的干预措施，并可能与其他更常见的具有相似生物学机制的疾病相关。

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.