KINASE-MEDIATED SIGNALING PATHWAYS IN NEURONAL APOPTOSIS
KINASE-MEDIATED SIGNALING PATHWAYS IN NEURONAL APOPTOSIS
批准号:
6639703
负责人:
MARY LOU VALLANO
金额:
$26.48万
依托单位国家:
美国
项目类别:
财政年份:
2000
资助国家:
美国
项目状态:
已结题
起止时间:
2000-07-01 至 2005-06-30
中文摘要
描述(摘自申请者的摘要):我们正在研究
激酶介导的信号通路促进神经元存活并防止
颗粒神经元原代培养中的细胞凋亡。相关的神经营养因子有
胰岛素样生长因子与脑源性神经营养因子
(BDNF)。谷氨酸是调节神经元的主要神经递质。
通过与不同的谷氨酸受体通道相互作用而发挥活性,
在此称为N-甲基-D-天冬氨酸(NMDA)和非NMDA受体。
这些药物与神经元血浆中各自受体的结合
膜启动细胞内信号级联的激活,调节
促凋亡或抗凋亡基因的转录。两者之间的平衡
这些基因产物最终决定了细胞的命运。早期颗粒细胞
发育,在神经元形成突触连接之前,它们依赖于
专门针对神经营养因子,存在于沐浴它们的血清中,用于
生死存亡。我们有新的证据表明该家族的特定亚型
磷脂敏感蛋白激酶(PKCs),称为非典型PKCs
(APKCs),是神经营养素依赖生存的关键组成部分
路径。我们对这些数据相当热情,因为几乎没有什么是
目前已知的APKCs的神经功能。此外,初步的
数据表明,抑制aPKCs会减少丝氨酸-133的磷酸化。
核转录因子CREB。此应用程序的一个目标是
扩展我们的研究,检查神经营养素依赖之间的联系
激活APKCs。CREB的磷酸化。和生存。在许多神经元中
兴奋性神经递质电刺激不足的人群
或者营养因子不足使细胞更有可能死亡。“钙调整点”
假说“假设”认为胞浆中大量的钙活动决定了
未成熟神经元需要营养因子抑制的程度
导致细胞凋亡的机制(Koike等人,1989)。因此,许多
在分离培养中生长的神经元类型可以从死亡中拯救出来,
由剥夺神经营养素诱导,通过在介质中包含
使钙离子持续升高。这些代理包括提升的KCI代理
通过电压敏感的钙通道(VSCCs)和直接作用于
NMDA受体通道(NRs)。我们有新的证据表明钙离子和
钙调蛋白依赖的激酶,命名为CaM KIV,其底物CREB是
这条钙依赖的信号通路的关键组成部分。
免疫细胞化学证据还表明,这些治疗可以诱导
CaM KIV从胞核到胞浆的再分布。第二个目标是
这个应用程序是为了扩展我们的研究,检查
钙、CaM KIV对CREB的磷酸化,与存活率有关。磷酸化和
CREB的激活可能介导了抗凋亡基因的诱导,如
Bc1-2,或抑制促凋亡基因,如bax。这是第三个目标
应用是比较bc1-2和bax rnRNAs在
促进存活或凋亡的培养条件。
英文摘要
DESCRIPTION (From the applicant's abstract): We are studying the
kinase-mediated signaling pathways that promote neuronal survival and prevent
apoptosis in primary cultures of granule neurons. Relevant neurotrophins are
insulin-like growth factor (IGF-1) and brain-derived neurotrophic factor
(BDNF). Glutamate is the predominant neurotransmitter that regulates neuronal
activity through its interaction with different glutamate receptor-channels,
referred to herein as N-methyl-D-aspartate (NMDA) and non-NMDA receptors.
Binding of these agents to their respective receptors in the neuronal plasma
membrane initiates activation of intracellular signaling cascades that regulate
the transcription of pro-apoptotic or anti-apoptotic genes. The balance between
these gene products ultimately determines cell fate. Early in granule cell
development, before neurons have formed synaptic connections, they rely
exclusively on neurotrophic factors, present in the serum that bathes them, for
survival. We have novel evidence that particular isoforms of the family of
phospholipid-sensitive protein kinases (PKCs), designated as atypical PKCs
(aPKCs), are critical components of the neurotrophin-dependent survival
pathway. We are quite enthusiastic about these data since almost nothing is
currently known about the neuronal functions of aPKCs. Moreover, preliminary
data indicate that inhibition of aPKCs reduces phosphorylation on serine-133 of
the nuclear transcription factor CREB. One goal of this application is to
extend our studies examining the linkage between neurotrophin-dependent
activation of aPKCs. phosphorvlation of CREB. and survival. In many neuronal
populations, inadequate electrical stimulation by excitatory neurotransmitters
or inadequate trophic factor make cell death more likely. A "Ca2+ set-point
hypothesis" postulates that the bulk cytosolic Ca2+ activity determines the
degree to which immature neurons require trophic factor to suppress the
mechanism responsible for apoptosis (Koike et al., 1989). Accordingly, many
types of neurons grown in dissociated culture can be rescued from death,
induced by neurotrophin deprivation, by inclusion of agents in the media that
produce a sustained elevation in Ca2+. These agents include elevated KCI acting
through voltage-sensitive Ca2+ channels (VSCCs) and NMDA acting directly upon
NMDA receptor channels (NRs). We have novel evidence that a Ca2+ and
calmodulin-dependent kinase, designated as CaM KIV, and its substrate CREB are
critical components of this Ca2+-dependent signaling pathway.
Immunocytochemical evidence also indicated that these treatments induce the
redistribution of CaM KIV from the nucleus to the cytosol. A second goal of
this application is to extend our studies examining the linkage between
calcium, CaM KIV phosphorvlation of CREB, and survival. Phosphorylation and
activation of CREB may mediate induction of anti-apoptotic genes, such as
bc1-2, or repression of pro-apoptotic genes, such as bax. A third goal in this
application is to compare the expression levels of bc1-2 and bax rnRNAs under
culture conditions promoting survival or apoptosis.
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Roscovitine triggers excitotoxicity in cultured granule neurons by enhancing glutamate release.
Roscovitine 通过增强谷氨酸释放来触发培养的颗粒神经元的兴奋性毒性。
DOI:
10.1124/mol.105.012732
发表时间:
2005
期刊:
Molecular pharmacology
影响因子:
3.6
作者:
[Monaco3rd,EdwardA, Vallano,MaryLou]
通讯作者:
Vallano,MaryLou
Reduced blockade by extracellular Mg(2+) is permissive to NMDA receptor activation in cerebellar granule neurons that model a migratory phenotype.
细胞外 Mg(2 ) 的阻断减少,允许模拟迁移表型的小脑颗粒神经元中 NMDA 受体激活。
DOI:
10.1111/j.1471-4159.2010.06746.x
发表时间:
2010
期刊:
Journal of neurochemistry
影响因子:
4.7
作者:
[Gerber,AdamM, Beaman-Hall,CarolM, Mathur,Anjili, Vallano,MaryLou]
通讯作者:
Vallano,MaryLou
Depolarization and Ca(2+) down regulate CB1 receptors and CB1-mediated signaling in cerebellar granule neurons.
去极化和 Ca(2) 下调小脑颗粒神经元中 CB1 受体和 CB1 介导的信号传导。
DOI:
10.1016/j.neuropharm.2005.11.012
发表时间:
2006
期刊:
Neuropharmacology
影响因子:
4.7
作者:
[Vallano,MaryLou, Beaman-Hall,CarolM, Bui,CuongJ, Middleton,FrankA]
通讯作者:
Middleton,FrankA
Ca2+ and CaM kinase regulate neurofilament expression.
Ca2 和 CaM 激酶调节神经丝表达。
DOI:
10.1097/00001756-200311140-00013
发表时间:
2003
期刊:
Neuroreport
影响因子:
1.7
作者:
[Bui,CuongJ, Beaman-Hall,CarolM, Vallano,MaryL]
通讯作者:
Vallano,MaryL
Transcriptional profiling of depolarization-dependent phenotypic alterations in primary cultures of developing granule neurons.
发育中的颗粒神经元原代培养物中去极化依赖性表型改变的转录谱。
DOI:
10.1016/j.brainres.2006.08.043
发表时间:
2006
期刊:
Brain research
影响因子:
2.9
作者:
[Bui,CuongJ, McGann,AlexandraC, Middleton,FrankA, Beaman-Hall,CarolM, Vallano,MaryLou]
通讯作者:
Vallano,MaryLou
A calcium/calcineurin signaling cascade regulates neuronal cannabinoid receptors
-
批准号:7575699
-
项目类别:
-
资助金额:$7.85万
-
财政年份:2008
-
负责人:MARY LOU VALLANO
-
依托单位:
A calcium/calcineurin signaling cascade regulates neuronal cannabinoid receptors
-
批准号:7474331
-
项目类别:
-
资助金额:$7.85万
-
财政年份:2008
-
负责人:MARY LOU VALLANO
-
依托单位:
Adolescent ethanol exposure and NMDA receptor maturation in cerebellum
-
批准号:7405402
-
项目类别:
-
资助金额:$7.85万
-
财政年份:2007
-
负责人:MARY LOU VALLANO
-
依托单位:
Adolescent ethanol exposure and NMDA receptor maturation in cerebellum
-
批准号:7256861
-
项目类别:
-
资助金额:$7.83万
-
财政年份:2007
-
负责人:MARY LOU VALLANO
-
依托单位:
KINASE-MEDIATED SIGNALING PATHWAYS IN NEURONAL APOPTOSIS
-
批准号:6203878
-
项目类别:
-
资助金额:$26.48万
-
财政年份:2000
-
负责人:MARY LOU VALLANO
-
依托单位:
KINASE-MEDIATED SIGNALING PATHWAYS IN NEURONAL APOPTOSIS
-
批准号:6540349
-
项目类别:
-
资助金额:$26.48万
-
财政年份:2000
-
负责人:MARY LOU VALLANO
-
依托单位:
KINASE-MEDIATED SIGNALING PATHWAYS IN NEURONAL APOPTOSIS
-
批准号:6394540
-
项目类别:
-
资助金额:$26.48万
-
财政年份:2000
-
负责人:MARY LOU VALLANO
-
依托单位:
EXCITOTOXIC MECHANISMS OF ETOH--NMDA RECEPTOR FUNCTION
-
批准号:2894193
-
项目类别:
-
资助金额:$7.54万
-
财政年份:1998
-
负责人:MARY LOU VALLANO
-
依托单位:
EXCITOTOXIC MECHANISMS OF ETOH--NMDA RECEPTOR FUNCTION
-
批准号:2615897
-
项目类别:
-
资助金额:$7.54万
-
财政年份:1998
-
负责人:MARY LOU VALLANO
-
依托单位:
DEVELOPMENTAL EXPRESSION OF CAM KINASE II ISOFORMS
-
批准号:3413944
-
项目类别:
-
资助金额:$9.34万
-
财政年份:1990
-
负责人:MARY LOU VALLANO
-
依托单位:
DEVELOPMENTAL EXPRESSION OF CAM KINASE II ISOFORMS
-
批准号:2266498
-
项目类别:
-
资助金额:$14.46万
-
财政年份:1990
-
负责人:MARY LOU VALLANO
-
依托单位:
DEVELOPMENTAL EXPRESSION OF CAM KINASE II ISOFORMS
-
批准号:2266499
-
项目类别:
-
资助金额:$15.19万
-
财政年份:1990
-
负责人:MARY LOU VALLANO
-
依托单位:
DEVELOPMENTAL EXPRESSION OF CAM KINASE II ISOFORMS
-
批准号:2266500
-
项目类别:
-
资助金额:$15.86万
-
财政年份:1990
-
负责人:MARY LOU VALLANO
-
依托单位:
DEVELOPMENTAL EXPRESSION OF CAM KINASE II ISOFORMS
-
批准号:3413943
-
项目类别:
-
资助金额:$9.3万
-
财政年份:1990
-
负责人:MARY LOU VALLANO
-
依托单位:
DEVELOPMENTAL EXPRESSION OF CAM KINASE II ISOFORMS
-
批准号:3413941
-
项目类别:
-
资助金额:$8.84万
-
财政年份:1990
-
负责人:MARY LOU VALLANO
-
依托单位:
CALMODULIN DEPENDENT KINASE AND SYNAPTIC FUNCTION
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批准号:2265324
-
项目类别:
-
资助金额:$9.36万
-
财政年份:1988
-
负责人:MARY LOU VALLANO
-
依托单位:
CALMODULIN DEPENDENT KINASE AND SYNAPTIC FUNCTION
-
批准号:3476800
-
项目类别:
-
资助金额:$9.0万
-
财政年份:1988
-
负责人:MARY LOU VALLANO
-
依托单位:
CALMODULIN DEPENDENT KINASE AND SYNAPTIC FUNCTION
-
批准号:3476798
-
项目类别:
-
资助金额:$8.3万
-
财政年份:1988
-
负责人:MARY LOU VALLANO
-
依托单位:
CALMODULIN DEPENDENT KINASE AND SYNAPTIC FUNCTION
-
批准号:3476797
-
项目类别:
-
资助金额:$8.72万
-
财政年份:1988
-
负责人:MARY LOU VALLANO
-
依托单位:
CALMODULIN DEPENDENT KINASE AND SYNAPTIC FUNCTION
-
批准号:3476799
-
项目类别:
-
资助金额:$8.3万
-
财政年份:1988
-
负责人:MARY LOU VALLANO
-
依托单位:
海外基金