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：
7760970
负责人：
RAUL A. URRUTIA
金额：
$ 35.9万
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 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7760970
关键词：
Affect Animals Apoptosis Apoptotic Area Arts Award Biological Cause of Death Cell Cycle Cell Death Cell physiology Cells Complex Data Development Diabetes Mellitus Diagnosis Disease Down-Regulation Enzymes Exocrine pancreas Family Foundations Functional disorder Future 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 Investigation 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 Patients Pharmaceutical Preparations Play 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 disorder prevention effective therapy field study gene discovery gene repression innovation insight interest member novel public health relevance receptor research study superoxide dismutase 1 transcription factor KLF13

项目摘要

DESCRIPTION (provided by applicant): 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 TGF¿-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) TGF¿ ?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 TGF¿-inducible KLF repressors) and their role in modulating the expression of members of the TGF¿ 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 histone-deacetylases, 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 TGF¿ ?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 ¿ 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 TGF¿ 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 TGF¿ 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. PUBLIC HEALTH RELEVANCE: These investigations represent a defined strategy to discover how pancreatic cancer, a painful and deadly disease that ranks 4th as the cause of death by cancer in USA, arises. Patients affected by this cancer die within 3 to 6 months after the diagnosis, and currently, no effective treatment exists for this disease. However, we are optimistic that our studies will build the foundation for future treatment and perhaps even the prevention of this disease.

描述（由申请人提供）：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。该提案旨在定义新型 TGF 调节外分泌胰腺细胞生长的基本机制？ - 我们实验室发现的诱导型 KLF 锌指阻遏蛋白最近引起了人们的极大兴趣，因为我们之前的观察使我们在三个重要领域有了发现：1) 细胞。生长抑制，2) 转录抑制，以及 3) TGF¿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 KLF11 的新型辅助调节分子（TGFβ 诱导型 KLF 阻遏物亚家族的结构和功能范式）及其在调节 TGF 成员的表达¿我们选择这个焦点是因为它在提供新的机制信息方面具有很高的潜力，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制很少，并且对其在外分泌胰腺细胞生长和疾病的调节中的作用有初步了解。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 TGF 成员来调节肿瘤转化。 ?我们的目标将测试以下假设：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：与 G 蛋白的相互作用 ¿亚基调节 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 TGF¿已知参与正常细胞生长和/或肿瘤转化调节的信号蛋白家族。我们相信，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。具有细胞生长调节和 TGF¿考虑到我们的专业知识、之前发表的工作和当前的初步数据，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。为了更好地了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、形态发生和调节肿瘤转化：这些研究代表了发现胰腺细胞如何发生变化的明确策略。癌症是一种痛苦而致命的疾病，在美国癌症死亡原因中排名第四，患有这种癌症的患者会在诊断后3至6个月内死亡，但目前尚无有效的治疗方法。我们乐观地认为，我们的研究将为未来治疗甚至预防这种疾病奠定基础。