The Role of CREBRF on Hypothalamic Function

CREBRF 对下丘脑功能的作用

• 批准号: 10351771
• 负责人: Krystle Anne Frahm
• 金额: $ 11.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-23 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351771
• 关键词: Acute; Address; Adult; Antibodies; Award; Behavior; Behavioral; Binding; Binding Sites; Body Weight; Body mass index; Brain region; C-terminal; CREB3 gene; CRISPR/Cas technology; Cells; Chromatin; Complement; Complex; Data; Development; Diabetes Mellitus; Disease; Eating; Ensure; Female; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomics; Glucocorticoids; Goals; Grant; Hawaiian population; Health; Height; Human; Hypothalamic structure; Knock-in; Maternal Behavior; Metabolic; Mission; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neuroanatomy; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Output; Pathway interactions; Phenotype; Physiology; Polynesian; Prevention strategy; Public Health; Quality of life; Regulation; Research; Research Personnel; Role; Samoan; Signal Transduction; Testing; United States National Institutes of Health; Variant; Weight Gain; Work; acute stress; antibody detection; anxiety-like behavior; behavioral outcome; behavioral phenotyping; biological adaptation to stress; career; diabetes risk; disorder prevention; genome-wide analysis; improved; insight; male; mouse model; novel; programs; recruit; response; risk variant; stressor; transcriptome; whole genome

Obesity is escalating at an alarming rate and is a major contributor to associated to multiple serious health problems such as Type 2 diabetes. Interesting, a missense variant in humans was identified in the poorly understood gene CREBRF to increase BMI while protecting from developing diabetes. CREBRF is a transcriptional co-regulator that is expressed centrally and within the hypothalamus, whose neurons integrate information from other brain regions as well as the periphery to control many homeostatic functions such as food intake and stress responses. Furthermore, loss of CREBRF in mice impacts hypothalamic output observed by a reduction in body weight, glucocorticoid levels after an acute stressor, and anxiety-like behaviors. Therefore, the overall objective of this proposal is to determine how CREBRF impacts hypothalamic function by determining its localization and recruitment to the genome in a brain region critical for stress responses. Our central hypothesis is that CREBRF functions as a transcriptional co-regulator to regulate gene expression, ultimately influencing metabolic and behavioral outcomes. The central hypothesis will be tested using the novel CREBRF3xFLAG mouse model and our expertise in neuroanatomy, genome-wide analysis, and behavioral phenotyping to achieve the following sub-aims: 1.) to determine the impact of CREBRF on the transcriptional response to acute stress within the hypothalamus, 2.) to systematically characterize hypothalamic CREBRF by determining its regulation and localization during acute stress, and 3.) to perform baseline phenotyping for this novel CREBRF3xFLAG global mouse model. Using antibodies to detect the 3x-FLAG tag, we expect to gain a substantial amount of information about CREBRF while ensuring this small tag does not impact CREBRF function and interpretation of our results. This research will provide deep understanding for a relatively unknown gene and advance our understanding for how CREBRF impacts physiology and behavior. These Sub-Aims will complement ongoing K01 research and expand our research capabilities to further understand the role of CREBRF on hypothalamic function, ultimately impacting output. Support provided by this R03 Award will allow Dr. Frahm to continue to build her independent research program by generating preliminary data for a competitive R01 grant submission.

肥胖正在以惊人的速度升级，并且是与多种严重健康相关的主要因素。 比如2型糖尿病。有趣的是，人类的一种错义变体在穷人中被鉴定出来。 了解基因CREBRF增加BMI，同时防止患糖尿病。CREBRF是一个 一种转录辅助调节因子，在中枢和下丘脑内表达，其神经元整合 来自其他大脑区域以及外围的信息来控制许多自我平衡功能， 摄入量和压力反应。此外，小鼠中CREBRF的缺失影响了下丘脑的输出， 体重减轻、急性应激后糖皮质激素水平降低和焦虑样行为。因此 这项建议的总体目标是通过确定CREBRF如何影响下丘脑功能， 定位和募集到对应激反应至关重要的大脑区域的基因组中。我们的核心假设 CREBRF作为转录辅助调节因子调节基因表达，最终影响 代谢和行为结果。将使用新型CREBRF 3xFLAG小鼠检验中心假设 模型和我们在神经解剖学，全基因组分析和行为表型方面的专业知识，以实现 以下分目标：1.）为了确定CREBRF对急性应激的转录反应的影响， 下丘脑，2.）通过确定其调节系统地表征下丘脑CREBRF， 急性应激期间的定位，以及3.）对这种新型CREBRF 3xFLAG全局进行基线表型分析 小鼠模型使用抗体来检测3x-FLAG标签，我们期望获得大量的信息 同时确保这个小标签不会影响CREBRF的功能和对我们结果的解释。 这项研究将为一个相对未知的基因提供深入的了解，并促进我们对 CREBRF如何影响生理和行为。这些分目标将补充正在进行的K 01研究， 扩大我们的研究能力，以进一步了解CREBRF对下丘脑功能的作用，最终 影响产量。R 03奖提供的支持将使Frahm博士能够继续建立她的独立 研究计划通过生成竞争R 01赠款提交的初步数据。