Mechanisms underlying Notch function in hypoxia

项目摘要/摘要 缺氧(氧(O2)剥夺)是一个关键的病理因素，通常会导致发病率和 美国和世界范围内的死亡率。到目前为止，治疗或预防氧气剥夺引起的损伤的策略是 非常有限。因此，了解调节对氧气缺乏的耐受性或敏感性的机制是 对于制定有效的治疗策略至关重要。我们和其他人已经证明了Notch信号 在调节易感性的细胞和分子机制方面发挥重要作用。 对低氧压力的耐受性。我们的初步研究表明：a)Notch信号在 调节耐低氧能力，即携带Notch功能丧失等位基因的黑腹果蝇是“超敏感”的 相反，携带功能增益等位基因的果蝇对低氧有显著的抵抗力；b)神经元或神经胶质细胞- Notch的特殊激活将幼稚的苍蝇从致命的氧气剥夺浓度中拯救出来；以及c)Notch 信号是一种进化上保守的机制，调节对低氧环境的适应，不仅在 果蝇和人类也是如此。此外，各种研究还表明，Notch活性在 预防心肌损伤，调节心肌梗死后的修复和再生。然而， Notch调控缺氧反应的分子机制还不是很清楚。在……里面 在目前的应用中，我们将确定遗传修饰物或效应物，以确定Notch下游 神经细胞和神经胶质细胞缺氧条件下细胞存活的调控机制。我们选择了D。 因为我们有相当多的经验和数据使用这种基因 模型，因为它是一个剖析机制的伟大模型。基于我们对人类的基因组研究 在高海拔地区，我们最近发现了一组进化上保守的基因，它们调节 人和果蝇的低氧适应。此前的研究表明，这些基因中的一些 (例如，FGFR和HES1)相互作用，调节/调节Notch信号。我们将利用这些保守的基因 探讨它们在调节Notch诱导的低氧耐受中的作用。由于这些基因高度保守， 这些研究用于翻译和临床应用的可能性变得更高。 我们的具体目标是：1)确定调节Notch对O2的耐受性的遗传修饰物 剥夺；以及2)确定Notch介导的转录机制介导的Notch功能 在特定的神经元和神经胶质细胞中耐缺氧。我们的目标是确定新的机制 潜在的Notch-授予的低氧耐受性，将导致更好的治疗或 预防。

Project Summary/Abstract Hypoxia (oxygen (O2) deprivation) is a critical pathological factor that often leads to morbidity and mortality in the USA and world-wide. To date, strategies to treat or prevent O2 deprivation-induced injury is very limited. Thus, understanding the mechanisms regulating tolerance or susceptibility to O2 deprivation is crucial for developing effective therapeutic strategies. We and others have demonstrated that Notch signaling plays an important role in regulating the cellular and molecular mechanisms underlying susceptibility or tolerance to hypoxic stress. Our preliminary studies have shown that a) Notch signaling plays a critical role in regulating hypoxia tolerance, i.e., D. melanogaster carrying Notch loss-of-function alleles are “super-sensitive” to low O2, and, in contrast, flies carrying gain-of-function alleles are remarkably resistant; b) neuronal- or glial- specific activation of Notch rescues naïve flies from a lethal concentration of O2 deprivation; and c) Notch signaling is an evolutionarily conserved mechanism regulating adaptation to low O2 environments not only in Drosophila but also in humans. In addition, various studies have also shown that Notch activity is critical in preventing cardiac injury and regulating repair and regeneration after myocardial infarction. However, the molecular mechanisms underlying the role of Notch in regulating hypoxia response are not well understood. In the current application, we will identify genetic modifiers or effectors to determine the Notch downstream mechanisms that regulate cell survival under O2 deprivation in neuronal and glial cells. We chose D. melanogaster to perform such studies since we have considerable experience and data using this genetic model, and because it is a great model to dissect mechanisms. Based on our genomic work on human dwellers at high altitude, we have recently discovered a group of evolutionarily conserved genes that regulate hypoxia adaptation in both humans and Drosophila. Previous studies have shown that some of these genes (e.g., FGFR and HES1) interact and regulate/mediate Notch signaling. We will use these conserved genes to probe their role in regulating Notch-conferred hypoxia tolerance. Since these genes are highly conserved from flies to humans, the likelihood of these studies for translational and clinical applications becomes much higher. Our Specific Aims are: 1) to identify genetic modifiers that regulate Notch-conferred tolerance to O2 deprivation; and 2) to determine Notch-mediated transcriptional mechanisms mediating Notch function in hypoxia tolerance in specific neuronal and glial cells. Our goal is to identify novel mechanisms underlying Notch-conferred hypoxia tolerance that would lead to targets and strategies for better treatment or prevention.