Ceramide Metabolism and Photoreceptor Homeostasis

神经酰胺代谢和感光器稳态

• 批准号: 8446421
• 负责人: USHA R ACHARYA
• 金额: $ 35.16万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446421
• 关键词: Affect; Afferent Neurons; Animal Model; Apoptosis; Arrestins; Biochemical; Biological Models; Blindness; Calcium; Cell membrane; Cell physiology; Ceramidase; Ceramides; Defect; Degenerative Disorder; Differentiation and Growth; Disease; Drosophila genus; Endocytosis; Engineering; Enzymes; Equilibrium; Eukaryotic Cell; Excision; Eye; Eye diseases; Failure; Family; Fibroblasts; Foundations; Ganglioside Sialidase Deficiency Disease; Genes; Genetic; Goals; Hereditary Sensory Neuropathy; Homeostasis; Human; Impairment; Inherited; Lead; Learning; Light; Lipids; Maintenance; Mammalian Cell; Measurement; Mediating; Membrane; Metabolism; Modeling; Multiprotein Complexes; Mutate; Mutation; Organism; Pathway interactions; Patients; Peripheral; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipase C; Photoreceptors; Phototransduction; Process; Protein Family; Proteins; Proteolysis; Recycling; Regulation; Retinal; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Rhodopsin; Role; Second Messenger Systems; Serine; Services; Signal Transduction; Sphingolipidoses; Sphingolipids; Sphingosine; Structure; Testing; Transcript; Transferase; Transgenic Organisms; Vision; Visual; Work; angiogenesis; base; ceramide kinase; design; dihydrosphingosine 1-phosphate; enzyme pathway; fly; insight; loss of function; mutant; novel therapeutics; phospholipase C beta; photoreceptor degeneration; protein function; public health relevance; receptor; second messenger; serine palmitoyltransferase; sphingosine 1-phosphate; sphingosine kinase; synaptic function; therapeutic development; trafficking; treatment strategy; visual photoreceptor; visual process; visual processing

DESCRIPTION (provided by applicant): Sphingolipids are essential components of all eukaryotic cell membranes; many of them like ceramide, sphingosine 1-phosphate are also bioactive lipids regulating cellular functions ranging from apoptosis to angiogenesis. The importance of sphingolipids is clinically well appreciated due to their deregulation in Sphingolipidoses. They are a large group of inherited diseases caused by defects in enzymes of sphingolipid metabolism and are associated with retinal impairment. Mutations in serine palmitoyl transferase 1, the rate-limiting enzyme of the sphingolipid biosynthetic pathway leads to Hereditary Sensory Neuropathy, a common degenerative disorder of peripheral sensory neurons. Several studies have recently identified mutations in a ceramide kinase like gene leading to autosomal recessive Retinitis Pigmentosa in patients. This proposal is based on our findings that enzymes of the sphingolipid biosynthetic pathway and their metabolites are important regulators of Drosophila photoreceptor structure, function, and modulation of this pathway can suppress retinal degeneration in a set of phototransduction mutants. Maintenance of ceramide level in photoreceptors by enzymes of this pathway is important for viability of photoreceptors, visual signaling through Phospholipase C, and turnover of Rhodopsin 1 in photoreceptors. Based on these findings, the focus of this project is to continue to understand how sphingolipid metabolism regulates photoreceptor homeostasis. The specific aims of the project are: (1) To obtain further insight into ceramide mediated disruption of signaling and degeneration in photoreceptors. (2) To understand how flux through the sphingolipid biosynthetic pathway regulates photoreceptor homeostasis by generating and characterizing mutants in serine palmitoyltransferase. (3) To study the role of sphingosine kinases and their metabolites in trafficking of Rhodopsin 1 and Transient Receptor Potential (TRP) and in maintenance of calcium homeostasis mediated by TRP family of proteins. Delineation of the functions of sphiolipids in Drosophila photoreceptors and phototransduction will provide the groundwork for our long-term objective to comprehensively understand functions of sphingolipids, the enzymes that control teir metabolism, and the processes through which these enzymatic networks integrate into other pathways involved in sustenance of a eukaryotic organism. This will provide a strong foundation for design and development of therapeutic strategies for treatment of diseases associated with sphingolipids.

描述（由申请人提供）：鞘脂是所有真核细胞膜的重要组成部分；其中许多像神经酰胺一样，1-磷酸鞘氨醇也是调节细胞功能的生物活性脂质，从凋亡到血管生成。鞘脂的重要性在临床上得到了很好的赞赏，因为它们在鞘脂中放松管制。它们是由鞘脂代谢酶缺陷引起的一大批遗传疾病，与视网膜障碍有关。丝氨酸棕榈酰转移酶1中的突变，鞘脂生物合成途径的速率限制酶导致遗传性感觉神经病，这是外围感觉神经元的常见退化性疾病。最近的几项研究已经鉴定出在神经酰胺激酶（如基因）中的突变，从而导致患者的常染色体隐性视网膜炎。该建议基于我们的发现，即鞘脂生物合成途径的酶及其代谢产物是果蝇光感受器结构，功能和调节的重要调节剂，可以抑制一组光转导突变体中的视网膜变性。通过该途径的酶维持光感受器中的神经酰胺水平对于光感受器的生存能力，通过磷脂酶C的视觉信号传导以及光感受器中的Rhodopsin 1的周转至关重要。基于这些发现，该项目的重点是继续了解鞘脂代谢如何调节感光体稳态。该项目的具体目的是：（1）进一步了解神经酰胺介导的光感受器中信号传导和变性的破坏。 （2）了解通过鞘脂生物合成途径的通量如何通过在丝氨酸棕榈酰转移酶中产生和表征突变体来调节感光体稳态。 （3）研究鞘氨醇激酶及其代谢产物在运输Rhodopsin 1和瞬时受体电位（TRP）以及维持TRP蛋白质介导的钙稳态的作用。 Delineation of the functions of sphiolipids in Drosophila photoreceptors and phototransduction will provide the groundwork for our long-term objective to comprehensively understand functions of sphingolipids, the enzymes that control teir metabolism, and the processes through which these enzymatic networks integrate into other pathways involved in sustenance of a eukaryotic organism.这将为设计和开发与鞘脂相关的疾病的治疗策略的设计和开发提供了坚实的基础。

项目成果

Mitochondrial degeneration and not apoptosis is the primary cause of embryonic lethality in ceramide transfer protein mutant mice.

• DOI: 10.1083/jcb.200807176
• 发表时间: 2009-01-12
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Wang, Xin;Rao, Raghavendra Pralhada;Kosakowska-Cholody, Teresa;Masood, M. Athar;Southon, Eileen;Zhang, Helin;Berthet, Cyril;Nagashim, Kunio;Veenstra, Timothy K.;Tessarollo, Lino;Acharya, Usha;Acharya, Jairaj K.
• 通讯作者: Acharya, Jairaj K.

Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors.

• DOI: 10.1083/jcb.201004098
• 发表时间: 2011-02-21
• 期刊: The Journal of cell biology
• 作者: Yonamine I;Bamba T;Nirala NK;Jesmin N;Kosakowska-Cholody T;Nagashima K;Fukusaki E;Acharya JK;Acharya U
• 通讯作者: Acharya U

Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity.

• DOI: 10.1083/jcb.201404118
• 发表时间: 2014-07-21
• 期刊: The Journal of cell biology
• 作者: Rahman M;Nirala NK;Singh A;Zhu LJ;Taguchi K;Bamba T;Fukusaki E;Shaw LM;Lambright DG;Acharya JK;Acharya UR
• 通讯作者: Acharya UR

Phosphatidic acid phospholipase A1 mediates ER-Golgi transit of a family of G protein-coupled receptors.

• DOI: 10.1083/jcb.201405020
• 发表时间: 2014-07-07
• 期刊: The Journal of cell biology
• 作者: Kunduri G;Yuan C;Parthibane V;Nyswaner KM;Kanwar R;Nagashima K;Britt SG;Mehta N;Kotu V;Porterfield M;Tiemeyer M;Dolph PJ;Acharya U;Acharya JK
• 通讯作者: Acharya JK

CDase is a pan-ceramidase in Drosophila.

CDase 是果蝇中的一种泛神经酰胺酶。

• DOI: 10.1091/mbc.e10-05-0453
• 发表时间: 2011
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Yuan,Changqing;Rao,RaghavendraPralhada;Jesmin,Nahid;Bamba,Takeshi;Nagashima,Kunio;Pascual,Alberto;Preat,Thomas;Fukusaki,Eiichiro;Acharya,Usha;Acharya,JairajK
• 通讯作者: Acharya,JairajK