EMMPRIN: from biology to molecular mechanism

EMMPRIN：从生物学到分子机制

基本信息

批准号：
8643256
负责人：
ELAN Z EISENMESSER
金额：
$ 28.63万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8643256
关键词：
Address Behavior Biochemical Biological Biology Blood Carcinoma Cell surface Cells Cleaved cell Clinical Research Complex Disease Disease Progression Extracellular Matrix Feedback Health Heart Human Immunoglobulin Domain Inflammation Inflammatory Integral Membrane Protein Lead Length Link Malignant Neoplasms Matrix Metalloproteinases Membrane Molecular Neoplasm Metastasis Play Protein Family Protein Isoforms Proteins Recombinant Proteins Recombinants Resolution Retinal Retinoblastoma Roentgen Rays Role Signal Pathway Signal Transduction Solutions Structure System Testing Therapeutic Tissues Transcript base biophysical techniques cancer cell cell motility cell transformation cellular targeting cytokine dimer extracellular glycosylation in vivo insight leukemia melanoma new therapeutic target overexpression tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) is highly expressed in multiple cancers and inflammatory disorders where it stimulates secretion of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines. EMMPRIN is amongst a subset of unique proteins that exist as a transmembrane protein but is released by cells in multiple uncharacterized forms. These extracellular forms have already been linked to at least half a dozen cancers and have been shown to contribute to a positive feedback loop during cancer progression. Thus, identifying the specific extracellular forms of EMMPRIN, characterizing how each of these forms contributes to disease progression, and identifying their cellular targets would significantly contribute to our understanding of cancer and inflammation. We have taken an integrative approach to fully characterize EMMPRIN and its role in disease progression by combining biological, biochemical, and atomic resolution studies. Our biological studies have already identified several extracellular forms of EMMPRIN in human blood and released by cancer cells that and the specific MMPs/cytokines secreted by these forms will be fully characterized here (Aim 1). To this end, we have developed recombinant expression systems that produce all the necessary proteins. We will then identify the cellular targets of these EMMPRIN forms by utilizing our recombinant proteins and characterize their interactions (Aim 2). Finally, we have begun solving the X-ray crystal structure and characterizing the solution behavior of a retinal-specific EMMPRIN isoform that contributes to retinoblastoma and here we will characterize this isoform both biophysically and biologically (Aim 3). Since EMMPRIN over-expression results in the deregulation of entire protein families integrally involved in the progression of multiple diseases, our combined biological and biophysical approach will fully characterize extracellular EMMPRIN at the biological and molecular levels, respectively.

描述（由申请人提供）：细胞外基质金属蛋白酶诱导酶（EMMPRIN）在多种癌症和炎症性疾病中高度表达，其中它刺激了基质金属蛋白酶（MMPS）和炎性细胞因子的分泌。 Emmprin是作为跨膜蛋白而存在的独特蛋白质子集之一，但由细胞以多种未表征的形式释放。这些细胞外形式已经与至少六个癌症有关，并已被证明在癌症进展过程中有助于阳性反馈循环。因此，识别emmprin的特定细胞外形式，表征每种形式如何促进疾病进展，并确定其细胞靶标会极大地有助于我们对癌症和炎症的理解。我们采取了一种综合方法来充分表征艾姆普林及其在疾病进展中的作用，通过结合生物学，生化和原子分辨率研究。我们的生物学研究已经鉴定出人类血液中的几种细胞外艾米普林形式，并由癌细胞释放，这些形式分泌的特定MMP/细胞因子将在这里得到充分表征（AIM 1）。为此，我们开发了产生所有必要蛋白质的重组表达系统。然后，我们将通过利用我们的重组蛋白并表征它们的相互作用来识别这些Emmprin形式的细胞靶标（AIM 2）。最后，我们已经开始求解X射线晶体结构，并表征了视网膜特异性Emmprin同工型的溶液行为，从而有助于视网膜细胞瘤，在这里，我们将在生物物理和生物学上表征这一点（AIM 3）。由于EMMPRIN的过表达导致整个蛋白质家族的放松调节，该蛋白质一直涉及多种疾病的进展，因此我们的生物学和生物物理方法将分别在生物学和分子水平上分别完全表征细胞外Emmprin。