Therapeutic targeting of stratifin structure and function

Stratifin 结构和功能的治疗靶向

基本信息

批准号：
8457985
负责人：
Jian-Ting Zhang
金额：
$ 29.14万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8457985
关键词：
Adriamycin PFS Affect Apoptosis Apoptotic Binding Biochemical Cancer Center Cancer cell line Cell Cycle Cell Cycle Checkpoint Cells Chemicals Chemosensitization Chemotherapy-Oncologic Procedure Clinical DNA Damage DNA Double Strand Break DNA Repair DNA damage checkpoint Development Dimerization Ectopic Expression Environment Goals Homo Human Indiana Lead Malignant Neoplasms Malignant neoplasm of pancreas Mitoxantrone Molecular Mutation Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Play Principal Investigator Proteins Radiation Radiation therapy Research Role Series Structure Testing Therapeutic Therapeutic Agents Universities Work base cancer cell cancer therapy cellular targeting chemotherapy dimer drug discovery drug mechanism drug sensitivity experience human SFN protein inhibitor/antagonist interest knock-down outcome forecast pancreatic cancer cells protein protein interaction public health relevance response screening small hairpin RNA small molecule success survivin therapeutic target tool virtual

项目摘要

DESCRIPTION (provided by applicant): Lack of response to chemo and/or radiation-induced apoptosis is a major problem for successful therapy of human cancers such as pancreatic cancer. Recently, we found that the expression of stratifin is elevated in a series of drug-selected cancer cell lines that are less sensitive to drug-induced apoptosis and its expression level negatively correlates with the drug sensitivity level of these cells. Knocking-down with shRNA and enforced ectopic expression of stratifin both confirmed the cause-effect relationship between stratifin expression and drug insensitivity. The long-term goal of our study is to understand the molecular mechanisms of drug and/or radiation-induced apoptosis in pancreatic cancers and to sensitize cancer cells to these treatment-induced apoptosis. The immediate goal of this study is to investigate the role of stratifin in cellular response to drug or radiation-induced apoptosis and to target stratifin for drug discovery to enhance the response of pancreatic cancer cells to therapeutic treatment. The hypotheses to be tested in this study are that the elevated expression of stratifin in pancreatic cancer cells decreases cellular response to drug or radiation-induced apoptosis by binding to and affecting important proteins for survival and that this effect can be reversed by targeting stratifin using small molecule inhibitors. To this end, four specific aims will be accomplished: (1) to determine if increased stratifin expression also causes decrease in cellular response to radiation-induced apoptosis; (2) to determine if increased stratifin expression regulates Chk2 which, in turn, regulates cell cycle checkpoint for DNA repair and survival; (3) to determine the mechanism of dimerization and if the dimerization is required for the function of stratifin; and (4) to discover and test small chemical compounds targeting stratifin dimerization for chemosensitization. The excellent scientific environment at Indiana University Bren and Melvin Simon Cancer Center, the extensive experience of the principal investigator in studying cellular responses to drug- induced apoptosis, and the generous institutional support will contribute enormously to the likelihood of success of this project. The information and probes obtained from this study will help us understand the role of stratifin in apoptosis in cancer chemotherapy. This work will also lead us to the discovery of therapeutic agents that may help sensitize cancers to drug and radiation therapy and probes for investigating protein-protein interactions.

描述（由申请人提供）：缺乏对化学和/或辐射诱导的凋亡的反应是成功治疗胰腺癌等人类癌症的主要问题。最近，我们发现，在一系列药物选择的癌细胞系中，对药物诱导的细胞凋亡敏感且其表达水平与这些细胞的药物敏感性水平负相关。用shRNA敲击并强化地层蛋白的异位表达都证实了Stratifin表达与药物不敏感性之间的原因效应。我们研究的长期目标是了解胰腺癌中药物和/或辐射诱导的凋亡的分子机制，并使癌细胞对这些治疗诱导的凋亡敏感。这项研究的直接目的是研究Stratifin在细胞对药物或辐射诱导的细胞凋亡的反应中的作用，并靶向Stratifin进行药物发现，以增强胰腺癌细胞对治疗治疗的反应。在这项研究中要检验的假设是，胰腺癌细胞中地层蛋白的表达升高可通过与重要蛋白结合并影响重要的蛋白质来降低细胞对药物或辐射诱导的细胞凋亡的反应，并且可以使用小分子抑制剂靶向地层靶向，从而逆转这种作用。为此，将实现四个特定目标：（1）确定层蛋白表达增加是否还会导致细胞对辐射诱导的细胞凋亡的反应降低；（2）确定增加的层蛋白表达是否调节CHK2，进而调节细胞周期检查点的DNA修复和存活；（3）确定二聚化的机理以及是否需要二聚化的功能；（4）发现和测试针对地层二聚化化学敏化的小型化合物。印第安纳大学Bren和Melvin Simon Cancer Center的出色科学环境，这是主要研究者研究药物诱导凋亡的细胞反应的广泛经验，以及慷慨的机构支持将有助于该项目成功的可能性。从这项研究中获得的信息和探针将有助于我们了解层蛋白在凋亡在癌症化疗中的作用。这项工作还将导致我们发现治疗剂，这些治疗剂可能有助于使癌症对药物和放射疗法以及研究蛋白质蛋白质相互作用的探针敏感。