BDNF AND MeCP2 in Autonomic Dysfunction

BDNF 和 MeCP2 在自主神经功能障碍中的作用

• 批准号: 7912099
• 负责人: David M. Katz
• 金额: $ 19.37万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912099
• 关键词: Action Potentials; Acute; Adult; Afferent Neurons; Afferent Pathways; Anatomy; Animal Model; Arrhythmia; Attention; Autonomic Dysfunction; Autonomic nervous system disorders; Baroreflex; Biological Models; Blocking Antibodies; Blood Pressure; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Calcium; Cardiac; Cardiovascular system; Cell Culture Techniques; Cell Nucleus; Cells; Cephalic; Characteristics; Clinical; Data; Defect; Electric Stimulation; Exhibits; Fiber; Frequencies; Genes; Genetic; Heart; Heart Rate; Homeostasis; Human; In Vitro; Knockout Mice; Laboratories; Lead; Learning; Life; Light; Mediating; Messenger RNA; Methods; Methyl-CpG-Binding Protein 2; Microinjections; Molecular; Molecular Target; Mus; Mutant Strains Mice; Nerve; Neuronal Dysfunction; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Nucleus solitarius; Null Lymphocytes; Pathway interactions; Patients; Pattern; Phenotype; Physiology; Preparation; Pressoreceptors; Property; Proteins; Rattus; Reflex action; Regulation; Research; Research Design; Research Personnel; Rett Syndrome; Rodent; Role; Sensory; Sensory Ganglia; Series; Signal Transduction; Site; Slice; Source; Sudden Death; Synapses; Synaptic Transmission; Testing; Time; Visceral; Work; autonomic reflex; base; blood pressure regulation; depressed; design; drug development; gene function; improved; in vivo; mutant; patch clamp; postsynaptic; programs; research study; response; synaptic function; tool; trafficking; transmission process; voltage clamp

DESCRIPTION (provided by applicant): The aim of the proposed research is to define how genetic loss of MeCP2, the gene responsible for Rett Syndrome (Rett), disrupts Brain Derived Neurotrophic Factor (BDNF) signaling in autonomic reflex pathways in the brainstem nucleus tractus solitarius (nTS). nTS is the principal site at which visceral sensory input is integrated in the brainstem and defects in nTS function have been proposed to underlie autonomic dysfunctions in Rett. Normally, visceral sensory neurons, located in the nodose-petrosal cranial sensory ganglia (NPG), synthesize and release high levels of BDNF, a putative transcriptional target of MeCP2. However, we recently found that expression and secretion of BDNF are severely impaired in NPG neurons of MeCP2 null mice. In particular, levels of BDNF protein are markedly depressed in mutant NPG neurons compared to wildtype cells, although levels of BDNF mRNA are normal. In addition, mutant cells exhibit abnormally high levels of constitutive BDNF release. As a result, we hypothesize that transynaptic BDNF signaling by visceral sensory neurons in nTS is disrupted by genetic loss of MeCP2. Moreover, recent studies in our laboratory indicate that BDNF can potently modulate the excitability of second order relay neurons in nTS and that this modulation is impaired in MeCP2 null mice. On the basis of these findings we hypothesize that dysregulation of BDNF signaling by NPG neurons contributes to the life-threatening autonomic dysfunctions associated with Rett. However, almost nothing is known about mechanisms of BDNF signaling in nTS in general and the role of MeCP2 in particular. The proposed studies are designed, therefore, to elucidate 1) basic mechanisms of synaptic modulation by BDNF in nTS, using brainstem slice preparations, 2) how loss of MeCP2 function alters BDNF dependent signaling by visceral sensory neurons and synaptic transmission in nTS and 3) the role of BDNF in nTS mediated autonomic reflexes in vivo. In addition, we have recently found that the BDNF deficit in MeCP2 null NPG neurons is reversible in vitro. Therefore, the proposed studies are also designed to develop potential strategies for increasing or restoring normal levels of BDNF expression in MeCP2 null mutants in vivo. By elucidating the roles of BDNF and MeCP2 in autonomic reflex pathways, the proposed research aims to shed light on cellular and molecular mechanisms relevant to understanding and improved management of Rett Syndrome and other disorders of autonomic homeostasis. In particular, it is hoped that defining how MeCP2 disrupts BDNF dependent signaling by visceral sensory neurons will lead to identification of new molecular targets for drug development aimed at improving autonomic function in Rett patients..

描述（由申请人提供）：拟议研究的目的是确定MeCP2（Rett综合征（Rett）的基因）的遗传缺失如何破坏脑干孤束核（nTS）自主反射通路中的脑源性神经营养因子（BDNF）信号传导。nTS是内脏感觉输入整合在脑干中的主要部位，并且已经提出nTS功能的缺陷是Rett中自主神经功能障碍的基础。正常情况下，内脏感觉神经元，位于结节岩颅感觉神经节（NPG），合成和释放高水平的BDNF，一个假定的转录靶点的MeCP2。然而，我们最近发现，BDNF的表达和分泌的MeCP 2敲除小鼠的NPG神经元严重受损。特别是，与野生型细胞相比，突变型NPG神经元中BDNF蛋白的水平显著降低，尽管BDNF mRNA的水平是正常的。此外，突变细胞表现出异常高水平的组成型BDNF释放。因此，我们推测，跨突触BDNF信号转导内脏感觉神经元在nTS被破坏的MeCP2的遗传损失。此外，我们实验室最近的研究表明，BDNF可以有效地调节nTS中的二级中继神经元的兴奋性，并且这种调节在MeCP2缺失小鼠中受损。基于这些发现，我们推测NPG神经元对BDNF信号的失调导致了与Rett相关的危及生命的自主神经功能障碍。然而，对于nTS中BDNF信号传导的机制，特别是MeCP2的作用，几乎一无所知。因此，所提出的研究旨在阐明1）使用脑干切片制备物，BDNF在nTS中的突触调节的基本机制，2）MeCP 2功能的丧失如何改变内脏感觉神经元的BDNF依赖性信号传导和nTS中的突触传递，以及3）BDNF在体内nTS介导的自主反射中的作用。此外，我们最近发现，在MeCP2空NPG神经元中的BDNF缺陷在体外是可逆的。因此，所提出的研究也旨在开发潜在的策略，以增加或恢复正常水平的脑源性神经营养因子表达的MeCP2无效突变体在体内。通过阐明BDNF和MeCP2在自主反射通路中的作用，拟议的研究旨在阐明与理解和改善Rett综合征和其他自主稳态紊乱相关的细胞和分子机制。特别是，希望确定MeCP2如何破坏内脏感觉神经元的BDNF依赖性信号传导，将导致确定用于药物开发的新分子靶点，旨在改善Rett患者的自主神经功能。