Src hypoactivity as a mediator of various molecular alterations leading to NMDAR

Src 活性低下作为导致 NMDAR 的各种分子改变的介质

基本信息

批准号：
10054787
负责人：
Karin Borgmann-Winter
金额：
$ 21.49万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-11-12 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054787
关键词：
Src hypoactivity mediator various molecular

项目摘要

DESCRIPTION (provided by applicant): The N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis is one of the leading postulates for the pathophysiology of schizophrenia (SCZ) and is supported by numerous pharmacologic, behavioral and genetic studies. Nevertheless, we have little insight into specific alterations in NMDAR signaling and its mechanistic basis in SCZ patients. This is a critical knowledge gap, which has impeded further development of this hypothesis and limited our efforts to identify specific therapeutic interventions. (Preliminary Data) As direct evidence for altered NMDA receptor (NMDAR) signaling, we found decreased NMDA/Glycine induced tyrosine phosphorylation of NMDAR subunit 2 (GluN2) and reduced downstream signaling in the postmortem dorsal lateral prefrontal cortex (DLPFC) of SCZ cases. These changes are not associated with decreased NMDARs but with reduced activity of a cascade of kinases- Src kinase, protein kinase C and Pyk2- which in concert decrease GluN2 tyrosine phosphorylation. We found multiple molecular alterations in the DLPFC of SCZ cases; increased PSD-95, increased erbB4 activity, decreased dysbindin -1 and RPTPa, each of which can induce Src hypoactivity. (Hypotheses) We hypothesize that hypoactivity of Src in the NMDAR complex (Src-NR) reduces GluN tyrosine phosphorylation and is caused by altered protein interactions in a network of Src-NR-associated proteins ( the Src-NR interactome), which can be leveraged to modify behavioral phenotypes of NMDAR hypoactivity. (Approach) We propose a human-rodent translation strategy, by which we analyze disease related alterations in postmortem brains and examine their underlying mechanisms in rodent studies. Aim 1 will further examine postmortem brains of an elderly and mid-life SCZ cohorts to identify molecular alterations in the Src-NR interactome in SCZ, Aim 2 will determine the role of protein interactions in Src-NR hypoactivity and test rescue strategies in ex vivo preparations of rodent and human postmortem tissues and Aim 3 will determine SCZ related behavior and EEG phenotypes of Src-/- mice and test if Src enhancement can rescue such phenotypes in vivo.

描述（由申请人提供）：N-甲基-D-天冬氨酸（NMDA）受体功能减退假说是精神分裂症（SCZ）病理生理学的主要假设之一，并得到了大量药理学、行为和遗传学研究的支持。对 SCZ 患者 NMDAR 信号传导的具体改变及其机制基础知之甚少，这是一个关键的知识差距，它阻碍了这一假设的进一步发展，并限制了我们识别的努力。（初步数据）作为 NMDA 受体 (NMDAR) 信号传导改变的直接证据，我们发现 NMDA/甘氨酸诱导的 NMDAR 亚基 2 (GluN2) 酪氨酸磷酸化减少，并且死后背侧外侧前额皮质 (DLPFC) 中的下游信号传导减少。这些变化与 NMDAR 的减少无关，但与一系列激酶（Src 激酶、蛋白激酶）的活性降低有关。 C 和 Pyk2- 共同降低了 SCZ 病例 DLPFC 中的多种分子改变；PSD-95 增加，erbB4 活性增加，dysbindin -1 和 RPTPa 减少，其中每一个都可以导致 Src 活性降低。 ) 我们发现 NMDAR 复合物 (Src-NR) 中 Src 的活性低下会降低 GluN 酪氨酸磷酸化，并导致通过改变 Src-NR 相关蛋白网络（Src-NR 相互作用组）中的蛋白质相互作用，可用于改变 NMDAR 活性低下的行为表型（方法）我们提出了一种人类-啮齿动物翻译策略，并通过该策略进行分析。目标 1 将进一步检查老年人和中年 SCZ 群体的死后大脑，以确定 Src-NR 相互作用组的分子变化。 SCZ、目标 2 将确定蛋白质相互作用在 Src-NR 低活性中的作用，并测试啮齿动物和人类死后组织的离体制备中的救援策略，目标 3 将确定 Src-/- 小鼠的 SCZ 相关行为和 EEG 表型，并测试是否Src 增强可以在体内挽救此类表型。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biochemical fractionation and stable isotope dilution liquid chromatography-mass spectrometry for targeted and microdomain-specific protein quantification in human postmortem brain tissue.

生化分级分离和稳定同位素稀释液相色谱-质谱法用于人类死后脑组织中的靶向和微域特异性蛋白质定量。

DOI：
发表时间：
2012-12
期刊：
影响因子：
0
作者：
MacDonald, Matthew L;Ciccimaro, Eugene;Prakash, Amol;Banerjee, Anamika;Seeholzer, Steven H;Blair, Ian A;Hahn, Chang
通讯作者：
Hahn, Chang

Ceftriaxone reverses ketamine-induced lasting EEG and astrocyte alterations in juvenile mice.

头孢曲松可逆转幼年小鼠中氯胺酮诱导的持久脑电图和星形胶质细胞的改变。