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GATA-6: Key Regulator of AEC Transdifferentiation

GATA-6：AEC 转分化的关键调节因子

基本信息

批准号：
7146011
负责人：
Zea Borok
金额：
$ 34.77万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-09-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7146011
关键词：
5&apos Flanking Region AGTR2 gene Ablation Address Adult Affinity Alveolar Apoprotein (C)Area Binding Binding Sites Biological Assay Biological Models Bleomycin Cell Culture System Cell Differentiation process Cell Proliferation Cell Shape Cells Complementary DNA Consensus Cuboidal Cell Cultured Cells Data Development Down-Regulation EMSA Epithelial Epithelial Cells Family Fingers GATA6 transcription factor Gases Genes Goals Growth Hyperplasia In Situ In Vitro Injury Lentivirus Vector Luciferases Lung Maintenance Mediating Modeling Molecular Nuclear Protein Nuclear Proteins Pathway interactions Phase Phenotype Population Primary Cell Cultures Protein Overexpression Range Recovery Regulation Relative (related person)Reporter Repression Repressor Proteins Research Personnel Role Site Small Interfering RNA Squamous Cell Surface System Transfection Transgenic Mice Transgenic Organisms Zea alveolar epithelium aquaporin 5 base cell type chromatin immunoprecipitation cofactor combinatorial in vitro Model insight keratinocyte growth factor lung injury member mutant novel novel therapeutics progenitor programs promoter repaired success surfactant transcription factor transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): It is generally believed that alveolar epithelial type II (AT2) cells serve as progenitors of type I (AT1) cells in development and following injury to restore the alveolar gas exchange surface. However, the transcriptional programs that mediate differentiation between alveolar epithelial cell (AEC) phenotypes are almost entirely unknown. We have developed well-defined primary cell culture systems in which AEC transdifferentiation in vitro can be experimentally modulated, providing an excellent model with which to dissect molecular pathways that regulate transitions between AT2 and AT1 cell phenotypes. The transcription factor (TF) GATA-6 has been shown to be essential for AT1 cell differentiation during development. The goal of this proposal is to investigate the role of GATA-6 in regulating transitions between AT2 and AT1 cell phenotypes through reciprocal activation and repression of differentiation-related genes, with the long-range objective of understanding how regulation of AEC differentiation contributes to maintenance and repair of adult alveolar epithelium following injury. We hypothesize that: 1) activation and repression of cell type-specific genes that accompany transitions between AT1 and AT2 cell phenotypes in alveolar epithelium in adult lung are modulated by reciprocal up- or down-regulation/interactions of TF; 2) changes in the relative expression/activity of GATA-6 regulate transitions between AT2 and AT1 cell phenotypes; and 3) combinatorial interactions of GATA-6 with other cofactors or cell-restricted TF determine the state of AEC differentiation. We will capitalize on our established in vitro culture systems and success in isolating both AT2 and AT1 cells, together with expertise in characterizing AEC differentiation, to explore these hypotheses by addressing the following Specific Aims: 1) investigate the role of GATA-6 expression in regulation of AEC differentiated phenotype, 2) determine effects of modulating GATA-6 expression on AEC differentiated phenotype, and 3) investigate regulation of AEC differentiation by characterizing interactions of GATA-6 with cell-type specific genes and other cell-restricted TF. The role of GATA-6 in AEC differentiation will be elucidated by evaluating its expression in isolated and cultured AEC and in situ, modulating GATA-6 expression and assessing effects on AEC phenotype, and characterizing its interactions with and promoter occupancy of an AT1 cell-specific gene, aquaporin-5, in AT2 vs. AT1 cells. These studies will provide novel insights into molecular programming of AEC differentiation, which will form the basis for further studies to develop new therapeutic strategies for recovery from lung injury.

描述（由申请人提供）：通常认为II型肺泡上皮（AT2）细胞在发育过程中和在损伤后恢复肺泡气体交换表面时充当I型（AT1）细胞的祖细胞。然而，介导肺泡上皮细胞（AEC）表型之间分化的转录程序几乎完全未知。我们开发了明确的原代细胞培养系统，其中可以通过实验调节体外 AEC 转分化，提供了一个出色的模型来剖析调节 AT2 和 AT1 细胞表型之间转变的分子途径。转录因子 (TF) GATA-6 已被证明对于 AT1 细胞在发育过程中的分化至关重要。本提案的目的是研究 GATA-6 通过分化相关基因的相互激活和抑制来调节 AT2 和 AT1 细胞表型转变中的作用，长期目标是了解 AEC 分化的调节如何有助于损伤后成人肺泡上皮的维持和修复。我们假设：1）伴随成人肺泡上皮中 AT1 和 AT2 细胞表型之间转变的细胞类型特异性基因的激活和抑制是通过 TF 的相互上调或下调/相互作用来调节的； 2) GATA-6相对表达/活性的变化调节AT2和AT1细胞表型之间的转变； 3) GATA-6 与其他辅助因子或细胞限制性 TF 的组合相互作用决定 AEC 分化的状态。我们将利用我们已建立的体外培养系统和分离 AT2 和 AT1 细胞的成功，以及表征 AEC 分化的专业知识，通过解决以下具体目标来探索这些假设：1) 研究 GATA-6 表达在调节 AEC 分化表型中的作用，2) 确定调节 GATA-6 表达对 AEC 分化表型的影响，3) 通过表征相互作用来研究 AEC 分化的调节具有细胞类型特异性基因和其他细胞限制性 TF 的 GATA-6。 GATA-6 在 AEC 分化中的作用将通过评估其在分离和培养的 AEC 中和原位的表达、调节 GATA-6 表达并评估对 AEC 表型的影响，以及在 AT2 和 AT1 细胞中表征其与 AT1 细胞特异性基因 aquaporin-5 的相互作用和启动子占据情况来阐明。这些研究将为 AEC 分化的分子编程提供新的见解，这将为进一步研究开发肺损伤恢复的新治疗策略奠定基础。

项目成果

期刊论文数量（87）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Progressive recruitment of Runx2 to genomic targets despite decreasing expression during osteoblast differentiation.

DOI：
10.1002/jcb.21900
发表时间：
2008-11-01
期刊：
JOURNAL OF CELLULAR BIOCHEMISTRY
影响因子：
4
作者：
Pregizer, Steven;Baniwal, Sanjeev K.;Yan, Xiting;Brook, Zea;Frenkel, Baruch
通讯作者：
Frenkel, Baruch

Sodium-dependent lysine flux across bullfrog alveolar epithelium.

穿过牛蛙肺泡上皮的钠依赖性赖氨酸通量。

DOI：
10.1152/jappl.1988.65.4.1655
发表时间：
1988
期刊：
Journal of applied physiology (Bethesda, Md. : 1985)
影响因子：
0
作者：
Kim,KJ;Crandall,ED
通讯作者：
Crandall,ED

Nanoparticle effects on rat alveolar epithelial cell monolayer barrier properties.

DOI：
10.1016/j.tiv.2007.04.003
发表时间：
2007-12
期刊：
Toxicology in vitro : an international journal published in association with BIBRA
影响因子：
0
作者：
N. Yacobi;H. Phuleria;L. Demaio;C. Liang;C. Peng;C. Sioutas;Z. Borok;Kwang-Jin Kim;E. Crandall
通讯作者：
N. Yacobi;H. Phuleria;L. Demaio;C. Liang;C. Peng;C. Sioutas;Z. Borok;Kwang-Jin Kim;E. Crandall

Conjugation with cationic cell-penetrating peptide increases pulmonary absorption of insulin.