Mechansims of Shroom2 function in development and disease

Shroom2 在发育和疾病中的功能机制

• 批准号: 9097892
• 负责人: EDWARD M MARCOTTE
• 金额: $ 23.48万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-09 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097892
• 关键词: Amino Acids; Animal Model; Arginine; Biological Assay; Cysteine; Defect; Development; Disease; Dynein ATPase; Etiology; Evolution; Genetic; Goals; Human; Intellectual functioning disability; Leucine; Limb structure; Microtubules; Minus End of the Microtubule; Missense Mutation; Modeling; Molecular; Motor; Motor Neurons; Mus; Muscle Fibers; Muscle Weakness; Mutant Strains Mice; Mutation; Nervous System Physiology; Patients; Phenotype; Positioning Attribute; Proline; Proteins; Proteomics; Rana; Role; Stretching; Testing; Time; Variant; Work; Xenopus; base; cell type; gain of function; human disease; in vivo; insight; loss of function; male; motor control; nervous system disorder; protein function; public health relevance; research study; screening

 DESCRIPTION (provided by applicant): The goal of this proposal is to understand the function of Shroom2 and to determine the mechanisms by which mutations in human SHROOM2 cause neurological disease in patients. The work is grounded by the observation that the Undiagnosed Disease Network Patient UDP_7490 has a mutation in SHROOM2 that associates with intellectual disability, limb-girdle muscle weakness, Babinsky sign, and delayed gross motor control. Strikingly, our collaborator has identified a similar association between SHROOM2 and neurological disease in a second patient. These phenotypes in these patients are highly informative because: 1) all of these phenotypes have been observed previously in humans or animal models with defects in the minus-end directed microtubule motor transport machinery, and 2) our prior work on Shroom2 suggests that this poorly understood protein controls the organization of microtubule minus- ends and microtubule-based transport in diverse cell types. On the basis of these findings, we propose two aims: 1) we will assess the effect of Shroom2 loss of function in model animals, and 2) we will use quantitative assays of Shroom2 function and unbiased proteomic approaches to determine the effect of disease associated mutations in SHROOM2. Together, these Aims will provide unprecedented molecular insights into the Shroom2 mechanism of action and will advance our understanding of a previously un-recognized neurological disorder in humans.

 描述（由适用提供）：该提案的目的是了解shroom2的功能，并确定人类施工中的突变引起患者神经系统疾病的机制。这项工作是基于观察到的，即未诊断的疾病网络患者UDP_7490在Shroom2中具有突变，该突变与智力障碍，肢体女生肌肉无力，Babinsky符号和延迟的总体运动控制相关联。令人惊讶的是，我们的合作者在第二名患者中确定了Shroom2和神经疾病之间的类似关联。这些患者中的这些表型具有很高的信息信息，因为：1）所有这些表型先前已经在人类或动物模型中观察到，在负端的定向微管运动机械中，并且2）我们先前在Shoome2上的工作表明，这种不良理解的蛋白质可以理解蛋白质的蛋白质控制微管末端和微管类型的蛋白质。根据这些发现，我们提出了两个目的：1）我们将评估模型动物功能丧失的效果，2）我们将使用shroom2功能的定量评估和无偏见的蛋白质组学方法来确定Shroom2中疾病相关突变的效果。这些目标共同将对施工机理提供前所未有的分子见解，并将促进我们对人类以前未经认可的神经系统疾病的理解。