Oleate-responsive gene regulatory networks governing peroxisome proliferation

描述（由申请人提供）：过氧化物酶体是动态的、必需的细胞器，其容纳许多受调节的代谢途径并对几种外部刺激产生显著反应。它们的功能和生物发生与许多人类健康问题有关，包括神经病理学、癌症、衰老、心脏病、肥胖和糖尿病。在后生动物中，过氧化物酶体的诱导剂包括脂肪、降血脂药物、非遗传毒性致癌物和发育过程。这些反应在转录水平上受到控制。作为我们长期目标的一部分，全面，定量了解细胞如何控制过氧化物酶体增殖，功能和生物发生，我们的目标是了解转录调控网络的反应条件下，诱导过氧化物酶体。在这里，我们提出了一个结合实验和数学建模的方法，专注于转录调控网络管理的响应S。酿酒酵母转化为油酸-诱导过氧化物酶体的条件。基于全基因组转录因子定位和随之而来的基因表达数据的综合分析的新方法的结果，我们已经生成了涉及四个转录因子的油酸响应的初步数学模型。我们建议在这些初步结果的基础上，通过额外的定量数据生成，模型指导的假设生成，使用有针对性的网络扰动和分析进行假设检验，以及迭代模型的改进和扩展。最终，这种细胞反应的定量和预测模型将告知过氧化物酶体生物发生的程序和复杂的基因调控网络，管理不同的细胞反应的原则。过氧化物酶体是细胞内细胞器，其生物发生和功能与许多人类问题有关，包括遗传性神经病变、衰老、癌症、心脏病、肥胖和糖尿病。此外，细胞中过氧化物酶体的大小、数量和含量受到调节，并且可以响应于诸如脂肪、降血脂药物、致癌物和细胞分化等因素而发生显著变化。了解过氧化物酶体动力学，生物起源和功能对于了解这些众多的人类疾病及其未来的治疗至关重要。

DESCRIPTION (provided by applicant): Peroxisomes are dynamic, essential organelles that house numerous regulated metabolic pathways and respond dramatically to several external stimuli. Their function and biogenesis are linked to many human health concerns including neuropathologies, cancer, aging, heart disease, obesity and diabetes. In metazoans inducers of peroxisomes include fats, hypolipidemic drugs, nongenotoxic carcinogens and developmental processes. These responses are controlled at the level of transcription. As part of our long term goal of a comprehensive, quantitative understanding of how cells control peroxisome proliferation, function and biogenesis, we aim to understand transcriptional regulatory network responses to conditions that induce peroxisomes. Here, we propose a combined experimental and mathematical modeling approach focused on the transcriptional regulatory network governing the response of S. cerevisiae to oleate - a condition that induces peroxisomes. Based on results from a novel approach to the integrative analysis of genome- wide transcription factor localization and consequent gene expression data, we have generated a preliminary mathematical model of the oleate response involving four transcription factors. We propose to build on these preliminary results by additional quantitative data generation, hypothesis generation guided by the model, hypothesis testing using targeted network perturbation and analysis, and iterative model refinement and expansion. Ultimately, quantitative and predictive models of this cellular response will inform the program of peroxisome biogenesis and the principles that underlie complex gene regulatory networks that govern divergent cellular responses. PUBLIC HEALTH RELEVANCE Peroxisomes are intracellular organelles whose biogenesis and function are linked to many human concerns, including inherited neuropathologies, aging, cancer, heart disease, obesity and diabetes. Moreover, the size, number and content of peroxisomes in a cell are regulated and can change dramatically in response to factors such as fats, hypolipidemic drugs, carcinogens and cell differentiation. Understanding peroxisome dynamics, biogenesis and function are critical to understanding these numerous human conditions and to their future treatment.