ATF5 in the developing pancreas and survival functions in the mature beta cell.

ATF5 在发育中的胰腺中发挥作用，并在成熟的 β 细胞中发挥生存作用。

• 批准号: 9096772
• 负责人: Christine Juliana
• 金额: $ 6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2017-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096772
• 关键词: Apoptotic; Architecture; Beta Cell; Binding; Cell Differentiation process; Cell Line; Cell Survival; Cell physiology; Cells; Chromatin; Data; Data Set; Development; Diabetes Mellitus; Diabetes prevention; Embryo; Embryonic Development; Endocrine; Family; Fractionation; Gene Expression Profiling; Genes; Health; Hematopoietic; Homeostasis; Human; Immunoprecipitation; Insulin; Islets of Langerhans; Link; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mediation; Mediator of activation protein; Mus; Mutation; Neurons; Oxidative Stress; Pancreas; Phenotype; Predisposition; Prevention; Preventive therapy; Regulation; Research; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Staging; Staining method; Stains; Stimulus; Stress; Structure; Tissues; Transcript; activating transcription factor; biological adaptation to stress; blood glucose regulation; endocrine pancreas development; islet; nutrient deprivation; olfactory sensory neurons; overexpression; pancreas development; response; transcription factor

DESCRIPTION (provided by applicant): Proper function, development, and survival of the pancreatic insulin secreting ?-cell is critical for the prevention of diabetes. Thus mediators of these functions are highly important in the understanding of diabetes development and for discovery of feasible therapies. Activating transcription factor 5 (ATF5) is a transcription factor that has demonstrated anti-apoptotic, pro-survival, and differentiation roles in olfactory sensory neurons, hematopoietic cells, and several cancers. Preliminary data indicate that ATF5 is expressed during embryonic pancreatic development, in mature ?-cells, and enriched in pancreatic islets. However, the role of ATF5 in the developing and mature pancreas is not known. Aim 1 of this proposal will determine the role of ATF5 in pancreatic development through morphological and gene expression analysis of the pancreas and islets of an available global Atf5-/- mouse compared to WT littermates throughout gestational development. Results will delineate the specific targets important for ATF5 in the development of the pancreas, endocrine compartment, and islet architecture. Preliminary data indicate that ATF5 is a direct target of regulation by PDX1 in the mature ? -cell. PDX1 is known to have pro-survival roles pertaining to ER stress susceptibility in the mature ? -cell. Aim 2 of this proposal will focus on the mediation of PDX1 pro-survival roles and targets regulated by ATF5 in the mature ? -cell in the context of stress stimuli (e.g. nutrient deprivation, oxidative stress, ER stress) known to be detrimental to the ?-cell. Rescue of phenotypes resulting from PDX1 deficiency by overexpression of ATF5 in mature ?-cells will reveal the role of ATF5 in PDX1 signaling pathways and pro- survival functions. ATF5 will be further characterized by immunofluorescent staining, immunoprecipitation, fractionation, and mass spectrometry to reveal previously unknown binding partners, subcellular localization within the cell, and mechanisms of activation. This proposal is important as a point of discovery for a new set of targets for manipulation of ? -cell survival in the context of deleterious stimuli as well as possible preventive therapies for diabetes.

描述（由申请人提供）：胰腺胰岛素分泌β细胞的正常功能、发育和存活对于预防糖尿病至关重要。因此，这些功能的调节因子对于理解糖尿病的发展和发现可行的疗法非常重要。激活转录因子 5 (ATF5) 是一种转录因子 已证明其在嗅觉感觉神经元、造血细胞和多种癌症中具有抗凋亡、促存活和分化作用。初步数据表明，ATF5 在胚胎胰腺发育过程中的成熟β细胞中表达，并在胰岛中富集。然而，ATF5 在发育和成熟胰腺中的作用尚不清楚。该提案的目标 1 将通过对现有的全球 Atf5-/- 小鼠与 WT 同窝小鼠在整个妊娠发育过程中的胰腺和胰岛进行形态学和基因表达分析，确定 ATF5 在胰腺发育中的作用。结果将描绘 ATF5 在胰腺、内分泌区室和胰岛结构发育中重要的具体目标。初步数据表明，ATF5是成熟的PDX1调控的直接靶标。 -细胞。已知 PDX1 具有与成熟 ? ER 应激敏感性相关的促生存作用。 -细胞。该提案的目标 2 将重点关注 PDX1 促生存作用和 ATF5 在成熟 ?已知对β细胞有害的应激刺激（例如营养剥夺、氧化应激、ER应激）背景下的β细胞。通过在成熟α-细胞中过表达ATF5来拯救由PDX1缺陷引起的表型将揭示ATF5在PDX1信号传导途径和促生存功能中的作用。 ATF5 将通过免疫荧光染色、免疫沉淀、分级分离和质谱进一步表征，以揭示以前未知的结合伴侣、细胞内的亚细胞定位和激活机制。该提案作为发现一组新的操纵目标的点很重要？ -有害刺激下的细胞存活以及可能的糖尿病预防疗法。