Diversity Supplement for Bernandie Jean: Neutral sphingomyelinases and bioactive ceramides

Bernandie Jean 的多样性补充：中性鞘磷脂酶和生物活性神经酰胺

• 批准号: 9752140
• 负责人: YUSUF AWNI HANNUN
• 金额: $ 5.97万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752140
• 关键词: Alzheimer' s Disease; Apoptotic; Binding Proteins; Binding Sites; Cancer Biology; Cancer Patient; Catalytic Domain; Cell Death; Cell physiology; Cells; Ceramides; Chemicals; Computer Simulation; Computing Methodologies; Crystallization; Development; Docking; Enzymes; Equilibrium; Future; Goals; Human; Lead; Lipids; Malignant Neoplasms; Membrane; Metabolism; Methods; Molecular; Neurologic; Neuroprotective Agents; Obstruction; Outcome; Parkinson Disease; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiological Processes; Production; Regulation; Research; Role; SPHK1 enzyme; Signal Pathway; Site; Sphingolipids; Sphingomyelinase; Sphingomyelins; Sphingosine; Structure; Therapeutic; Therapeutic Uses; Work; anti-cancer; cell growth; dihydroceramide desaturase; human disease; in vivo; inhibitor/antagonist; molecular dynamics; neuron loss; novel; screening; small molecule; sphingosine 1-phosphate; sphingosine kinase; tumorigenesis; virtual

An intricate balance existing within the various signaling pathways has to be maintained for survival and normal functioning of human cells. Detrimental effects causing human disease can occur due to obstruction in this equilibrium. For instance, an important signaling pathway is the sphingolipid metabolism pathway. Ceramide and sphingosine are both bioactive sphingolipids and have both been implicated in cell growth arrest. Ceramide is produced via two major pathways in cells: a slow de novo synthesis pathway that is catalyzed by ceramide synthases and by a relatively faster method wherein sphingomyelin is hydrolyzed by sphingomyelinases such as neutral sphingomyelinase 2 (nSMase2). Additionally, sphingosine kinase 1 (SK1), one of two sphingosine kinase enzymes, is a highly regulated enzyme due to SK1's critical role in the clearance of ceramide and sphingosine and the production of the bioactive sphingolipid, sphingosine-1-phosphate (S1P). Both nSMase2 and SK1 are membrane-associated enzymes that have been implicated in several cellular and physiological processes. The long-term goal of this project is to understand how the activities of nSMase2 and SK1 are regulated on a molecular basis and how these enzymes can be modulated pharmacologically for future therapeutic uses. Additionally, nSMase2 is an attractive target for anti-cancer and neuro-protective drugs as there are currently no known drug-like inhibitors of nSMase2. This project aims to understand the molecular parameters necessary for the development of nSMase2 and SK1 inhibitors. This proposal will investigate the hypothesis that: new putative selective inhibitors of nSMase2 and SK1 will be identified as therapeutics using the structural information obtained for the catalytic domains of nSMase2 and SK1 along with computational methods such as docking, virtual screening, and molecular dynamics. It is expected that this work will accomplish two goals: one goal is that this research will provide a proof-of-principle for targeting a novel site of nSMase2 involved in lipid activation and a novel site on SK1 to inhibit association with the membrane and ultimately stop the activation of SK1 and nSMase2. The second expected outcome is that this work will discover small molecules that are potent and specific inhibitors of SK1 and nSMase2 that can work in an in vivo setting. The existing crystal structures may afford in silico discovery or creation of therapeutic hit-to-lead compounds and chemical probes, or elucidation of a ligand's protein binding site. Additionally, this work can have a significant positive impact on cancer patients because of the potential use as alternative cancer therapeutics.

必须维持各种信号通路中存在的复杂平衡， 人类细胞的存活和正常功能。造成人类疾病的有害影响， 这是因为在这种平衡中存在障碍。例如，一个重要的信号通路是 鞘脂代谢途径神经酰胺和鞘氨醇都是具有生物活性的鞘脂 都与细胞生长停滞有关神经酰胺通过两种主要途径产生 在细胞中：一种缓慢的从头合成途径，由神经酰胺脱氢酶和 其中鞘磷脂被鞘磷脂酶水解的相对较快的方法， 中性鞘磷脂酶2（nSMase 2）。此外，鞘氨醇激酶1（SK 1），两种 鞘氨醇激酶，是一种高度调节的酶，由于SK 1的关键作用， 神经酰胺和鞘氨醇的清除以及生物活性鞘脂的产生， 鞘氨醇-1-磷酸（S1 P）。nSM酶2和SK 1都是膜相关酶 与细胞和生理过程有关。的长期目标 该项目旨在了解nSMase 2和SK 1的活性如何在分子水平上受到调节， 基础以及如何调节这些酶以用于未来的治疗用途。 此外，nSMase 2是抗癌和神经保护药物的有吸引力的靶点， 目前还没有已知的nSM酶2的药物样抑制剂。该项目旨在了解 开发nSMase 2和SK 1抑制剂所需的分子参数。这 该提案将研究以下假设：新的推定的选择性抑制剂nSMase 2和 SK 1将被鉴定为治疗剂，使用催化的结构信息。 沿着使用计算方法，如对接、虚拟 筛选和分子动力学。预计这项工作将实现两个目标： 目标是这项研究将为靶向nSMase 2的新位点提供原理验证 参与脂质活化和SK 1上的一个新位点，以抑制与膜的结合， 最终停止SK 1和nSMase 2的激活。第二个预期结果是， 这项工作将发现小分子是SK 1和nSMase 2的有效和特异性抑制剂 可以在活体环境下工作。现有的晶体结构可以提供在硅片上发现 或产生治疗性的命中先导化合物和化学探针，或阐明配体的 蛋白质结合位点。此外，这项工作可以对癌症产生重大的积极影响。 患者，因为作为替代癌症治疗的潜在用途。