ROLE OF AMP-ACTIVATED PROTEIN KINASE IN LAFORA AND WOLFF-PARKINSON-WHITE DISEASE

AMP 激活的蛋白激酶在 Lafora 和 Wolff-Parkinson-White 病中的作用

• 批准号: 7960502
• 负责人: Matthew S. Gentry
• 金额: $ 25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960502
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Affect; Apoptosis; Binding; Biochemical; Carbohydrates; Cells; Centers of Research Excellence; Cessation of life; Computer Retrieval of Information on Scientific Projects Database; Consensus; Cytoplasm; Diabetes Mellitus; Disease; Epilepsy; Event; Funding; Grant; Heart; Heart Hypertrophy; In Vitro; Institution; Lafora Disease; Maps; Metabolic Diseases; Molecular; Mutation; Neurons; Parkinson Disease; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Research; Research Personnel; Resources; Role; Source; Translating; United States National Institutes of Health; Wolff-Parkinson-White Syndrome; base; carbohydrate metabolism; catalyst; human disease; in vivo; insight; mouse model; novel; sensor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lafora disease (LD) is caused by mutations in the carbohydrate phosphatase laforin. A hallmark of LD is the accumulation of insoluble carbohyrate, called Lafora bodies (LBs), in the cytoplasm of cells. While LBs accumulate in most cells, apoptosis only occurs in neurons and this eventually leads to epilepsy and death of the patient. Wolff-Parkinson-White (WPW) syndrome is a cardiac hypertrophy caused by insoluble carbohydrate accumulations resulting from mutations in the cellular energy sensor and regulator AMP-activated protein kinase (AMPK). We recently identified both a phenotypic and biochemical connection between LD and WPW. We discovered that i) carbohyrate accumulations in LD and WPW are very similar, ii) laforin contains an AMPK consensus phosphorylation site, iii) AMPK phosphorylates laforin in vitro, and iv) carbohydrates increase AMPK kinase activity towards laforin. This proposal will define these events and determine the connection between LD and WPW. Specific Aim 1 will identify the conditions that promote phosphorylation in vivo and map the in vivo phosphorylation site(s). In specific Aim 2, we will determine if AMPK phosphorylation affects laforin binding to known substrates, the localization of laforin, and/or the phosphatase of laforin. In specific aim 3, we will determine the mechanism of carbohydrate stimulated AMPK kinase activity. In doing so, we will define the fold increase in AMPK-kinase activity, the carbohydrate(s) catalyst, and the substrates affected. Finally, we will translate these findings into a mouse model of LD. The studies proposed will define the connection between AMPK-WPW with laforin-LD. In addition, they will better characterize carbohydrate metabolism, which is at the heart of multiple metabolic disorders including diabetes, and yield insights into novel treatments.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 拉福拉病(LD)是由碳水化合物磷酸酶拉福林突变引起的。LD的一个特点是在细胞质中积累了不溶的碳水化合物，称为拉福拉小体(Lbs)。虽然Lbs在大多数细胞中积累，但细胞凋亡只发生在神经元中，这最终会导致癫痫和患者的死亡。沃尔夫-帕金森-怀特(Wolff-Parkinson-White，WPW)综合征是一种由细胞能量感受器和调节器AMP激活的蛋白激酶(AMPK)突变引起的不溶性碳水化合物积聚引起的心肌肥厚。我们最近发现了LD和WPW之间的表型和生化联系。我们发现：1)在LD和WPW中碳水化合物的积累非常相似，2)Laforin含有AMPK共同的磷酸化位点，III)AMPK在体外使Laforin磷酸化，IV)碳水化合物增加对Laforin的AMPK激酶活性。该提案将定义这些事件，并确定LD和WPW之间的联系。特定目标1将确定促进体内磷酸化的条件并绘制体内磷酸化位点图(S)。在特定目标2中，我们将确定AMPK磷酸化是否影响Laforin与已知底物的结合、Laforin的定位和/或Laforin的磷酸酶。在具体目标3中，我们将确定碳水化合物刺激AMPK激酶活性的机制。在这样做的过程中，我们将定义AMPK-K活性的倍增、碳水化合物(S)催化剂和受影响的底物。最后，我们将把这些发现转化为LD的小鼠模型。所提出的研究将确定AMPK-WPW和Laforin-LD之间的联系。此外，他们将更好地描述碳水化合物代谢的特征，这是包括糖尿病在内的多种代谢疾病的核心，并为新的治疗方法提供见解。