WHY DO MUTATIONS IN IKBKAP CAUSE FAMILIAL DYSAUTONOMIA?

为什么 IKBKAP 突变会导致家族性自主神经失调？

• 批准号: 9100936
• 负责人: Frances Lefcort
• 金额: $ 31.5万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100936
• 关键词: 3' Splice Site; Adrenal Medulla; Adult; Age; Age-Months; Apoptosis; Apoptotic; Ataxia; Ataxic Gait; Autonomic nervous system; Axon; Axonal Transport; Birth; Blindness; Cells; Complex; Degenerative Disorder; Development; Disease; Dorsal; Endocytosis; Exhibits; Failure; Familial Dysautonomia; Functional disorder; Fungiform Papilla; Gait Ataxia; Genes; Genetic Transcription; Goals; Health; Heart Arrest; Hereditary Disease; Hereditary Sensory Neuropathy; Homeostasis; Human; Hypothalamic structure; Kidney Failure; Knockout Mice; Lead; Limb structure; Lung; Messenger RNA; Mitotic; Modeling; Motor; Motor Neurons; Movement; Mus; Muscle; Musculoskeletal; Mutation; Nervous system structure; Neural Crest; Neural Crest Cell; Neuraxis; Neuromuscular Junction; Neurons; Nonsense-Mediated Decay; Organ; Orthostatic Hypotension; Pain; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Play; Pneumonia; Positioning Attribute; Post-Translational Protein Processing; Presynaptic Terminals; Proteins; Role; Sensory; Signal Transduction; Spinal Cord; Stem cells; Sudden Death; Sympathetic Ganglia; Symptoms; Synaptic Transmission; Syncope; System; Tachycardia; Temperature Sense; Testing; Therapeutic; Unconscious State; Unsteady Gait; Vomiting; arm; autonomic neuropathy; blood pressure regulation; foot; gene function; human disease; motor impairment; mouse model; nerve supply; neuron loss; neuronal cell body; neurotransmission; neurotrophic factor; novel; prevent; progenitor; protein function; response; retrograde transport; scoliosis; spinal nerve posterior root; vasculogenesis

DESCRIPTION (provided by applicant): The goal of this proposal is to understand why reductions in the level of the IKAP protein cause the Hereditary Sensory and Autonomic Neuropathy Type III, Familial Dysautonomia (FD; also called Riley Day Syndrome). This disease is both a developmental and a progressive disorder. It is marked by tachycardia, orthostatic hypotension which results in frequent fainting and autonomic vomiting "crises", pulmonary problems, renal failure and musculoskeletal manifestations including scoliosis, ataxia and weakness. This disease not only devastates the functioning of the Autonomic Nervous System, but also is marked by severe deficits in pain and temperature sensation and has CNS manifestations. FD is due to a mutation in the gene IKBKAP, in a splice acceptor site (IVS20+6T>C; 99.5% of patients) that causes the transcription of a truncated mRNA which is targeted for nonsense-mediated decay. The function of the encoded protein, IKAP, is unresolved. It clearly plays an essential role in that mice that are completely null for Ikbkap die by E10 due to failure in neurulation and vasculogenesis. To determine what role IKAP serves in the nervous system and why its absence results in FD, we have made 2 conditional-knock out mouse models for the disease in which Ikbkap is deleted either from the neural crest (using a Wnt1-cre), or from neurons in the central nervous system (CNS), but not the peripheral nervous system (PNS; using a Ta1tubulin-cre). The Wnt1-cre/Ikbkap mice die within 24 hrs of birth and analyses of their PNS demonstrates a recapitulation of the human disease with significant reductions in sympathetic, parasympathetic and TrkA+ pain and temperature sensing neurons and thus provides an excellent model for determining the developmental disruptions in the disease. We found that the reduction in PNS neurons during development is due to apoptosis of both progenitor cells and post-mitotic neurons. The Ta1tubulin-cre/Ikbkap also faithfully recapitulates classic, but distinct, hallmarks of FD including scoliosis, hind limb weakness, and gait ataxia. These mice die on average at 5 months and their condition degenerates as they age, thus they provide an excellent system in which to study the progressively degenerative mechanisms that mark FD. These results indicate not only is deletion of Ikbkap in the nervous system sufficient to cause FD, but that we have two independent models in which we can dissect the functions of IKAP in the CNS and PNS, during development vs. progression in the adult. Since the Autonomic Nervous system (ANS) is a circuit that includes both CNS and PNS components, we propose here to take a system wide approach to determine the function of IKAP in both the CNS and PNS. With an understanding of the key pathways which require IKAP, the long term goal is to develop strategies to prevent the progressive degeneration of both CNS and PNS neurons in FD and the other HSANs.

描述（由申请人提供）：该提案的目的是了解为什么IK​​AP蛋白水平的降低导致遗传性感觉和自主神经病III型，家庭功能障碍（FD；也称为Riley Day综合征）。这种疾病既是发育疾病，也是进行性疾病。它以心动过速，体位性低血压为特征，导致频繁晕倒和自主性呕吐“危机”，肺部问题，肾功能衰竭和肌肉骨骼骨骼表现，包括脊柱侧弯，共济失调和无力。这种疾病不仅破坏了自主神经系统的功能，而且还以严重的疼痛和温度感觉障碍，并具有CNS表现。 FD是由于基因IKBKAP中的突变引起的，在剪接受体位点（IVS20+6T> C； 99.5％的患者），导致截短的mRNA转录，该mRNA的靶向无义介导的衰减。编码蛋白IKAP的功能尚未解决。它显然在那个完全无效的ikbkkap死亡的老鼠中起着至关重要的作用 由E10由于神经和血管生成而失败。为了确定IKAP在神经系统中起什么作用以及为什么它在FD中导致其缺乏作用，我们为疾病中的疾病制作了2个有条件的敲除鼠标模型，其中IKBKAP是从神经波峰（使用Wnt1-cre）中删除的（使用Wnt1-cre），或者是从中枢神经系统（CNS）中的神经元（CNS）中的神经元（CNS），而不是外周神经系统（pns pns t tas）。 WNT1-CRE/IKBKAP小鼠在24小时内死亡，对PNS的分析显示了对人类疾病的概括，并显着降低了交感神经，副交感神经和TRKA+ TRKA+疼痛和温度感应神经元，并为确定疾病的发育破坏提供了出色的模型。我们发现，发育过程中PNS神经元的降低是由于祖细胞和有丝分裂后神经元的凋亡。 Ta1tubulin-cre/ikbkap还忠实地概括了经典，但独特的FD标志，包括脊柱侧弯，后肢弱点和步态共济失调。这些小鼠平均在5个月时死亡，其病情随着年龄的增长而退化，因此它们提供了一个出色的系统，可以在其中研究标记FD的逐渐退化机制。这些结果表明，不仅是在足以引起FD的神经系统中IKBKAP的缺失，而且我们有两个独立的模型，在该模型中，我们可以在成人的发展与进展过程中剖析CNS和PNS中IKAP的功能。由于自主神经系统（ANS）是包括CNS和PNS组件的电路，因此我们在这里提议采用系统广泛的方法来确定IKAP在CNS和PNS中的功能。了解需要IKAP的关键途径，长期目标是制定策略，以防止FD和其他HSAN中CNS和PNS神经元的进行性变性。