cAMP Signaling in Sympathoadrenal Cell Development

交感肾上腺细胞发育中的 cAMP 信号转导

• 批准号: 6621764
• 负责人: Ourania M. Andrisani
• 金额: $ 30.38万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621764
• 关键词: animal tissue; biological signal transduction; bone morphogenetic proteins; catecholamines; cell differentiation; cell proliferation; cyclic AMP; developmental genetics; dopamine beta monooxygenase; enzyme mechanism; gene expression; genetic promoter element; genetic transcription; mitogen activated protein kinase; neural crest; neuroendocrine system; neurogenesis; tissue /cell culture; transcription factor; tyrosine 3 monooxygenase

DESCRIPTION (provided by applicant): The long-term goal of the proposed studies addresses the interplay of the cAMP and BMP-2 signaling pathways in determining the differentiation of Neural Crest (NC) cells to the sympathoadrenal (SA) lineage, employing primary NC cultures. In separate studies, bone morphogenetic proteins (BMP-2, 4 and 7) and cAMP elevating agents were shown to stimulate SA cell development, characterized by the expression of tyrosine hydroxylase (TH), dopamineB-hydroxylase (DBH) and the synthesis of catecholamines (CA). Only recently, studies from our laboratory demonstrated that the cAMP signaling pathway modulates both positive and negative signals which influence SA cell development. Specifically, moderate activation of cAMP signaling, in synergy with BMP-2, promotes SA cell development and induces the expression of the SA lineage-determining gene Phox2a. By contrast, robust activation of cAMP signaling opposes, even in the presence of BMP-2, SA cell development and blocks the expression of the SA lineage-determining genes ASH-I and Phox2a. The objectives of the proposed studies investigate the molecular mechanisms by which cAMP acts as a bimodal switch on SA cell development. Aim 1 addresses the hypothesis that low-level cAMP signaling synergizes transcriptionally with BMP-2 signaling at the phox2a gene promoter, via synergistic interactions occurring between the transcription factors ASH-i and CREB, and the co-activator protein CBP. Aim 2 addresses the hypothesis that the antagonistic effect of high-level cAMP signaling on SA cell development involves the activation of the MAPK pathway, effecting the inhibition of the BMP-2-activated transactivators SMADs. The Specific Aims are: Aim 1: To determine whether the synergistic effect between BMP-2 and low-level activation of cAMP signaling, on SA cell development and Phox2a expression, is linked to the transcriptional function of the cAMP pathway. Aim 2: To define the mechanism of the antagonistic effect of high-level activation of cAMP signaling on the BMP-2 mediated ASH-I gene expression and SA cell development.

描述（由申请人提供）：拟议研究的长期目标