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（申请人提供）：鞘脂是所有真核细胞膜的重要成分；其中许多像神经酰胺、1-磷酸鞘氨醇也是调节细胞功能（从细胞凋亡到血管生成）的生物活性脂质。由于鞘脂在鞘脂沉积症中的失调，鞘脂的重要性在临床上得到了充分认识。它们是一大类由鞘脂代谢酶缺陷引起的遗传性疾病，与视网膜损伤有关。丝氨酸棕榈酰转移酶 1（鞘脂生物合成途径的限速酶）的突变会导致遗传性感觉神经病，这是一种常见的周围感觉神经元退行性疾病。最近的几项研究发现，神经酰胺激酶样基因的突变会导致患者患有常染色体隐性遗传性视网膜色素变性。该提议基于我们的发现，即鞘脂生物合成途径的酶及其代谢物是果蝇光感受器结构、功能的重要调节剂，并且该途径的调节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活力、通过磷脂酶 C 的视觉信号传导以及光感受器中视紫红质 1 的更新非常重要。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光感受器稳态。该项目的具体目标是：（1）进一步了解神经酰胺介导的光感受器信号传导破坏和变性。 (2) 了解鞘脂生物合成途径的通量如何通过生成和表征丝氨酸棕榈酰转移酶突变体来调节光感受器稳态。 (3) 研究鞘氨醇激酶及其代谢物在视紫红质1和瞬时受体电位(TRP)运输以及TRP家族蛋白介导的钙稳态维持中的作用。描述果蝇光感受器和光转导中鞘脂的功能将为我们的长期目标奠定基础，即全面了解鞘脂的功能、控制其代谢的酶以及这些酶网络整合到参与真核生物维持的其他途径的过程。这将为设计和开发治疗与鞘脂相关疾病的治疗策略奠定坚实的基础。

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