The Role of Zinc Finger Genes in Pancreatic Cell Growth

锌指基因在胰腺细胞生长中的作用

基本信息

批准号：
7623774
负责人：
RAUL A. URRUTIA
金额：
$ 29.09万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-25 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7623774
关键词：
Animals Apoptosis Apoptotic Area Arts Award Biological Cause of Death Cell Cycle Cell Death Cell physiology Cells Complex Data Development Diabetes Mellitus Disease Down-Regulation Enzymes Family Functional disorder G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Goals Grant Heterotrimeric G Protein Subunit Heterotrimeric GTP-Binding Proteins Histone Deacetylation Histones Homeostasis Human Insulin Knowledge Laboratories Learning Link Malignant Neoplasms Malignant neoplasm of pancreas Mammalian Cell Mediating Methodology Methylation Methyltransferase Modeling Molecular Morphogenesis Mutation Natural regeneration Neoplastic Cell Transformation Normal Cell Oxidative Stress Pain Pancreas Pancreatic Diseases Pancreatitis Pathology Pathway interactions Pharmaceutical Preparations Play Principal Investigator Process Proteins Publishing Regulation Regulator Genes Repression Repressor Proteins Research Role Signal Transduction Signaling Molecule Signaling Protein Techniques Testing Time Tumor Suppressor Proteins Work Zinc Fingers catalase cell growth cell growth regulation chromatin remodeling design field study gene repression innovation insight interest member novel programs receptor research study superoxide dismutase 1 transcription factor KLF13

项目摘要

Our long term goal is to discover mechanisms that mediate silencing of tumor suppressor pathways during the development of pancreatic cancer, the 4th leading cause of death by cancer in USA and an extremely painful disease. Congruent with this goal, this proposal seeks to define basic mechanisms underlying the regulation of exocrine pancreatic cell growth by novel TGFß-inducible KLF zinc finger repressor proteins discovered by our laboratory. KLF proteins have recently elicited significant interest because of their role in regulating gene expression, normal morphogenesis, and neoplastic transformation. Our previous observations led us to discoveries in three important areas: 1) cell growth suppression, 2) transcriptional repression, and 3) TGFß ?signaling. Now, our preliminary data supports a unifying theme by which these three areas may be linked, namely studies on novel coregulator molecules for KLF11 (the structural and functional paradigm of this subfamily of TGFß-inducible KLF repressors) and their role in modulating the expression of members of the TGFß superfamily of signaling molecules. We chose this focus because of its high potential for providing novel mechanistic information that can fuel advances in our field of study. Corepressors constitute a new and exciting area of research which recently exploded after the discovery of histonedeacetylases, methylases, and chromatin remodeling machines in mammalian cells. Few corepressors are known for KLF proteins, and rudimentary knowledge is available on their role in the regulation of exocrine pancreatic cell growth and diseases. Thus our central hypothesis is that novel protein interactions modulate the function of KLF11 in gene expression and/or cell growth regulation, as well as neoplastic transformation via the regulation of members from the TGFß ?superfamily of signaling molecules. Our aims will test the following hypothesis: Aim 1: Interaction with HP1 modulates the ability of KLF11 to regulate gene expression, cell growth, and neoplastic transformation; Aim 2: Interaction with the G protein ß subunit modulates the ability of KLF11 to regulate gene expression, cell growth, and neoplastic transformation, and ; Aim 3: KLF11 regulates the expression of targets from the TGFß family of signaling proteins known to be involved in the regulation of normal cell growth and/or neoplastic transformation. These experiments will use state-of-the-art cellular and molecular techniques for analyzing both transcriptional repression and cell growth. We believe that linking corepressors with cell growth regulation and TGFß signaling makes this proposal innovative, hypothesis driven, highly focused, biologically and medically relevant, and feasible taking into consideration our expertise, previous published work, and current preliminary data. We are optimistic successful completion of these studies will help to build a useful theoretical framework for better understanding morphogenetic pathways that are active in exocrine pancreatic cells and help to maintain their homeostasis, regulate morphogenesis, and modulate neoplastic transformation.

我们的长期目标是发现在胰腺癌的发展过程中介导肿瘤抑制通路沉默的机制，胰腺癌是美国癌症死亡的第四大原因，也是一种极其痛苦的疾病，与这一目标相一致，本提案旨在定义基本机制。外分泌胰腺细胞生长调节的基础我们实验室发现的新型 TGFβ 诱导型 KLF 锌指阻遏蛋白最近引起了人们的极大兴趣，因为它们在调节基因表达、正常形态发生和肿瘤转化中发挥着重要作用。 1) 细胞生长抑制，2) 转录抑制，以及 3) TGFβ 信号传导现在，我们的初步数据支持了一个可以将这三个领域联系起来的统一主题，即新颖的研究。 KLF11 的核心调节分子（TGFβ 诱导型 KLF 阻遏物亚家族的结构和功能范例）及其在调节 KLF11 成员表达中的作用我们选择这个焦点是因为它具有提供新的机制信息的巨大潜力，可以推动我们研究领域的进步，这是一个新的、令人兴奋的研究领域，在组蛋白脱乙酰酶的发现后，该领域最近得到了爆炸性的发展。哺乳动物细胞中的 KLF 蛋白、甲基化酶和染色质重塑机器很少为人所知，并且对其在调节中的作用也有初步了解。因此，我们的中心假设是，新的蛋白质相互作用调节 KLF11 在基因表达和/或细胞生长调节中的功能，以及通过调节 TGFβ 信号分子超家族的成员来调节肿瘤转化。我们的目标将检验以下假设：目标 1：与 HP1 的相互作用调节 KLF11 调节基因表达、细胞生长和肿瘤转化的能力；目标 2：相互作用；与 G 蛋白 β 亚基一起调节 KLF11 调节基因表达、细胞生长和肿瘤转化的能力；目标 3：KLF11 调节已知参与正常细胞调节的 TGFβ 信号蛋白家族靶标的表达这些实验将使用最先进的细胞和分子技术来分析转录抑制和细胞生长。考虑到我们的专业知识，TGFß 信号传导使该提案具有创新性、假设驱动性、高度针对性、生物学和医学相关性以及可行性，我们乐观地认为，这些研究的成功完成将有助于建立一个有用的理论框架，以更好地理解外分泌胰腺细胞中活跃的形态发生途径，并有助于维持其稳态、调节形态发生和调节肿瘤。转变。