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

描述（由申请人提供）：胰腺胰岛素分泌ß-细胞的正常功能、发育和存活对糖尿病的预防至关重要。因此，这些功能的介质对于了解糖尿病的发展和发现可行的治疗方法非常重要。激活转录因子5 （ATF5）是一种转录因子，在嗅觉感觉神经元、造血细胞和几种癌症中具有抗凋亡、促生存和分化作用。初步数据表明，ATF5在胚胎胰腺发育期间、成熟ß-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。本提案的目的1将通过对可用的全球ATF5 -/-小鼠的胰腺和胰岛进行形态学和基因表达分析，并将其与WT幼崽在整个妊娠发育过程中进行比较，确定ATF5在胰腺发育中的作用。结果将描述ATF5在胰腺、内分泌室和胰岛结构发育中重要的具体靶点。初步数据表明，ATF5是成熟ß-细胞中PDX1调控的直接靶点。已知PDX1在成熟ß-细胞中具有促进存活的作用，与内质网应激易感性有关。该提案的目标2将侧重于在已知对ß-细胞有害的应激刺激（例如营养剥夺、氧化应激、内质网络应激）的背景下，成熟ß-细胞中由ATF5调节的PDX1促生存作用和靶标的介导。通过在成熟ß-细胞中过表达ATF5来挽救由PDX1缺乏引起的表型，将揭示ATF5在PDX1信号通路和促生存功能中的作用。ATF5将通过免疫荧光染色、免疫沉淀、分离和质谱进一步表征，以揭示以前未知的结合伙伴、细胞内的亚细胞定位和激活机制。这一建议是一个重要的发现点，为在有害刺激的背景下操纵ß-细胞存活提供了一套新的靶点，也为糖尿病的预防治疗提供了可能。

DESCRIPTION (provided by applicant): Proper function, development, and survival of the pancreatic insulin secreting ß-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 ß-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 ß-cell. PDX1 is known to have pro-survival roles pertaining to ER stress susceptibility in the mature ß-cell. Aim 2 of this proposal will focus on the mediation of PDX1 pro-survival roles and targets regulated by ATF5 in the mature ß-cell in the context of stress stimuli (e.g. nutrient deprivation, oxidative stress, ER stress) known to be detrimental to the ß-cell. Rescue of phenotypes resulting from PDX1 deficiency by overexpression of ATF5 in mature ß-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 ß-cell survival in the context of deleterious stimuli as well as possible preventive therapies for diabetes.