Role of Programmed Cell Death10 (PDCD10) in p38 MAP kinase activation and PDK1 si

程序性细胞死亡 10 (PDCD10) 在 p38 MAP 激酶激活和 PDK1 si 中的作用

基本信息

  • 批准号:
    7844923
  • 负责人:
  • 金额:
    $ 22.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-01 至 2012-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Understanding and manipulating complex protein-protein interactions required for physiological signaling during angiogenesis and vasculogenesis is an important step in developing prevention and treatment for hemorrhagic stroke. Disruption of these interactions or dysregulation of signaling proteins can result in defective vascular formation and subsequent disease. Cerebral cavernous malformation (CCM) is an example of a vascular anomaly in the brain caused by disruptions of signaling molecules that occurs naturally in 0.1 to 0.5% of the population. Genetic mutations at three loci are responsible for the inherited development of CCM. They encode three CCM proteins: Krit1 (Krev interaction trapped-1), OSM (Osmosensing scaffold for MEKK3 or malcalvernin), and PDCD10 (Programmed cell death 10). We have found that all three CCM proteins interact with each other and form a signaling complex in the cell. PDCD10 stands out among these proteins because of its extremely conserved amino acid sequence from invertebrates to mammals. Mutations of PDCD10 represent about 10% of all CCM; however, the subsequent lesions are the most severe form. PDCD10 is also the only CCM protein that has no known domain or motif that would provide possible insight into function. Our long term goals are to understand how PDCD10 functions in physiologic vascular development and pathologic CCM development and to translate this basic knowledge from this CCM system to new preventive/therapeutic interventions for hemorrhagic stroke and other vascular malformations. We hypothesize that (1) PDCD10 regulates p38 activation through its interaction with OSM, and (2) PDCD10 participates in PDK1 signaling via its interactions with phospholipids, and PDK1. We further propose that these interactions are essential for endothelial migration and vessel formation. Two aims are proposed in this study including define the role of PDCD10 in endothelial p38 MAPK activation (Aim 1) and define the functional relationship between membrane phospholipid binding of PDCD10 and signaling through PDK1 (Aim 2). Using endothelial cell line, we will examine the functional changes resulting from PDCD10 knockdown using RNAi and mutants containing site-specific mutations that impact its ability to interact with OSM, phospholipids, and PDK1. The localized interaction of complex, activation of downstream kinases, as well as endothelial migration and vessel formation will also be examined. PUBLIC HEALTH RELEVANCE: Understanding and manipulating complex protein-protein interactions required for physiological signaling during angiogenesis and vasculogenesis is an important step in developing prevention and treatment for hemorrhagic stroke. These proposed studies will be one of the first to define the unknown function of PDCD10 protein. Mutations of PDCD10 gene contribute to a genetically-predisposed hemorrhagic stroke condition called Cerebral Cavernous Malformation (CCM). This work links the CCM condition to two important cell signaling cascades including p38 MAP kinase and PI3K/PDK1, and providing us to new therapeutic targets for hemorrhagic stroke.
描述(由申请人提供):了解和操纵血管生成和血管生成过程中生理信号所需的复杂蛋白质-蛋白质相互作用是开发出血性卒中预防和治疗的重要步骤。这些相互作用的破坏或信号蛋白的失调可导致有缺陷的血管形成和随后的疾病。脑海绵状血管畸形(CCM)是由信号分子破坏引起的脑血管异常的一个例子,在0.1%至0.5%的人群中自然发生。三个基因座的遗传突变是导致CCM遗传发展的原因。它们编码三种CCM蛋白:Krit 1(Krev相互作用捕获-1),OSM(MEKK 3或malcalvernin的渗透传感支架)和PDCD 10(程序性细胞死亡10)。我们已经发现,所有三种CCM蛋白相互作用,并在细胞中形成信号复合物。PDCD 10在这些蛋白质中脱颖而出,因为其从无脊椎动物到哺乳动物的氨基酸序列极其保守。PDCD 10的突变约占所有CCM的10%;然而,随后的病变是最严重的形式。PDCD 10也是唯一一种没有已知结构域或基序的CCM蛋白,这些结构域或基序可以提供对功能的可能了解。我们的长期目标是了解PDCD 10在生理性血管发育和病理性CCM发育中的作用,并将CCM系统的基本知识转化为出血性卒中和其他血管畸形的新预防/治疗干预措施。我们假设(1)PDCD 10通过与OSM的相互作用调节p38的活化,(2)PDCD 10通过与磷脂和PDK 1的相互作用参与PDK 1信号传导。我们进一步提出,这些相互作用是必不可少的内皮细胞迁移和血管形成。本研究提出两个目的,一是明确PDCD 10在内皮细胞p38 MAPK活化中的作用(目的1),二是明确PDCD 10与膜磷脂结合和PDK 1信号转导之间的功能关系(目的2)。使用内皮细胞系,我们将检查使用RNAi和含有位点特异性突变的突变体敲低PDCD 10所导致的功能变化,这些突变影响其与OSM、磷脂和PDK 1相互作用的能力。还将检查复合物的局部相互作用、下游激酶的激活以及内皮细胞迁移和血管形成。公共卫生关系:了解和操纵复杂的蛋白质-蛋白质相互作用所需的生理信号在血管生成和血管生成是一个重要的一步,在开发预防和治疗出血性中风。这些拟议的研究将是首批确定PDCD 10蛋白未知功能的研究之一。PDCD 10基因的突变导致了一种称为脑海绵状血管畸形(CCM)的遗传易感性出血性卒中。这项工作将CCM条件与包括p38 MAP激酶和PI 3 K/PDK 1在内的两个重要细胞信号级联联系起来,并为我们提供了出血性卒中的新治疗靶点。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Role of cytoskeletal proteins in cerebral cavernous malformation signaling pathways: a proteomic analysis.
  • DOI:
    10.1039/c3mb70199a
  • 发表时间:
    2014-07
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Baxter SS;Dibble CF;Byrd WC;Carlson J;Mack CR;Saldarriaga I;Bencharit S
  • 通讯作者:
    Bencharit S
Immediate placement of a porous-tantalum, trabecular metal-enhanced titanium dental implant with demineralized bone matrix into a socket with deficient buccal bone: a clinical report.
  • DOI:
    10.1016/j.prosdent.2014.09.022
  • 发表时间:
    2015-04
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bencharit S;Byrd WC;Hosseini B
  • 通讯作者:
    Hosseini B
Salivary proteins associated with hyperglycemia in diabetes: a proteomic analysis.
  • DOI:
    10.1039/c3mb70196d
  • 发表时间:
    2013-11
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bencharit S;Baxter SS;Carlson J;Byrd WC;Mayo MV;Border MB;Kohltfarber H;Urrutia E;Howard-Williams EL;Offenbacher S;Wu MC;Buse JB
  • 通讯作者:
    Buse JB
Development and applications of porous tantalum trabecular metal-enhanced titanium dental implants.
多孔钽小梁金属增强钛牙种植体的开发与应用
  • DOI:
    10.1111/cid.12059
  • 发表时间:
    2014-12
  • 期刊:
  • 影响因子:
    3.6
  • 作者:
    Bencharit S;Byrd WC;Altarawneh S;Hosseini B;Leong A;Reside G;Morelli T;Offenbacher S
  • 通讯作者:
    Offenbacher S
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

SOMPOP BENCHARIT其他文献

SOMPOP BENCHARIT的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('SOMPOP BENCHARIT', 18)}}的其他基金

Role of Programmed Cell Death10 (PDCD10) in p38 MAP kinase activation and PDK1 si
程序性细胞死亡 10 (PDCD10) 在 p38 MAP 激酶激活和 PDK1 si 中的作用
  • 批准号:
    7447261
  • 财政年份:
    2009
  • 资助金额:
    $ 22.2万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了