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 人类细胞的生存和正常功能。导致人类疾病的有害影响可能 由于这种平衡而发生的。例如，一个重要的信号通路是 鞘脂代谢途径。神经酰胺和鞘氨酸都是生物活性鞘脂 并且都与细胞生长停滞有关。神经酰胺是通过两种主要途径生产的 在细胞中：一种缓慢的从头综合途径，由神经酰胺合酶催化和 相对更快的方法，其中鞘磷脂被鞘磷脂酶水解 中性鞘磷脂酶2（NSMASE2）。此外，鞘氨醇激酶1（SK1），两个 鞘氨醇激酶酶是一种高度调节的酶，因为SK1在 神经酰胺和鞘氨醇的清除以及生物活性鞘脂的产生， 鞘氨酸1-磷酸盐（S1P）。 NSMASE2和SK1都是与膜相关的酶 与几个细胞和生理过程有关。长期目标 该项目是为了了解NSMase2和SK1的活动如何受到分子的调节 基础以及如何通过药理学调节这些酶以用于将来的治疗用途。 此外，NSMASE2是抗癌和神经保护药物的吸引人目标 目前尚无NSMase2的已知药物样抑制剂。该项目旨在了解 NSMASE2和SK1抑制剂的开发所需的分子参数。这 提案将调查以下假设：NSMASE2和 使用用于催化的结构信息将SK1鉴定为治疗剂 NSMASE2和SK1的域以及计算方法，例如对接，虚拟 筛选和分子动力学。预计这项工作将实现两个目标：一个 目的是，这项研究将为针对NSMASE2的新地点提供原则证明 参与脂质激活和SK1上的新位点，以抑制与膜和 最终停止SK1和NSMASE2的激活。第二个预期的结果是 工作将发现SK1和NSMASE2的有效抑制剂的小分子 可以在体内设置中起作用。现有的晶体结构在硅发现中可能负担得起 或创建治疗性命中至铅化合物和化学探针，或阐明配体的 蛋白质结合位点。此外，这项工作可能对癌症产生重大积极影响 患者由于潜在用作替代性癌症治疗剂而患者。