Biology of Fungal Melanin

真菌黑色素的生物学

• 批准号: 9032198
• 负责人: Arturo Casadevall
• 金额: $ 56.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032198
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Anabolism; Animals; Antifungal Agents; Architecture; Biological; Biological Process; Biology; Cell Wall; Cells; Cellular biology; Charge; Chitin; Chitosan; Clinical Trials; Code; Complex; Cryptococcus neoformans; Destinations; Development; Disease; Drug resistance; Effector Cell; Electromagnetic Energy; Electrons; Energy Transfer; Exobiology; Extracellular Space; Family; Foundations; Funding; Growth; Harvest; Host Defense Mechanism; Human; Immunity; Individual; Label; Laboratories; Lead; Light; Lipids; Melanins; Melanosomes; Meningitis; Metabolic; Molecular; Molecular Structure; Morphology; NMR Spectroscopy; Nucleic Acids; Organism; Outcome; Oxidants; Pathway interactions; Patients; Pigments; Planets; Plants; Polyenes; Polysaccharides; Population; Predisposition; Process; Production; Property; Proteins; Radiation; Research; Research Personnel; Resistance; Saccharomyces cerevisiae; Site; Structure; Sunlight; System; Tissues; Ultraviolet Rays; Vesicle; Vesicle Transport Pathway; Virulence; Virulence Factors; Work; base; drug development; extracellular; fungus; killings; melanoma; microbial; mutant; novel; pathogen; programs; public health relevance; scaffold; solid state nuclear magnetic resonance; targeted treatment; therapeutic target; tool; toxic metal

 DESCRIPTION (provided by applicant): Melanin is a pigment that performs a variety of functions and is found in the plant and animal kingdoms. In fungi melanin reinforces cell walls, shields against ultraviolet radiation as well as toxic metals, harnesses high energy electromagnetic radiation and contributes to virulence. Despite its importance, very little is known about the structure of melanin because it is insoluble and amorphous, making it difficult to analyze. In the previous funding period we described a new, melanin-based process for harnessing energy through the capture of radiation; we laid the foundation for a new melanoma therapy targeting melanin that is now in clinical trials; we demonstrated the remarkable ability of melanin to shield against radiation and provided a novel way to study the structure of melanin by solid-state NMR analysis; we discovered an extracellular vesicular transport in fungi (associated with the formation of a fungal "melanosome"). This research program renewal is focused on melanization in the human pathogenic fungus Cryptococcus neoformans, which is responsible for almost a million annual cases of meningitis worldwide, primarily in patients with AIDS. We will build on the achievements and tools of the previous funding period in order to focus on the fungal melanosome and the process of melanization. Three Specific Aims are proposed: 1) To generate a molecular definition for the cargo in melanizing vesicle populations; 2) To investigate the mechanism by which the fungal melanosome interacts with the cell wall; 3) To investigate the molecular structure of C. neoformans melanin assemblies on their cell-wall scaffold. C. neoformans melanin is critical for virulence and it is also a potential target for therapeutic drug development. Agents that target melanin are attractive because they could be applied against a broad array of pathogenic fungi.

 描述（由申请人提供）：黑色素是一种具有多种功能的色素，存在于植物和动物界中，黑色素可以增强细胞壁，屏蔽紫外线辐射和有毒金属，利用高能电磁辐射和。尽管黑色素很重要，但人们对它的结构知之甚少，因为它是不溶性和无定形的，这使得我们在之前的资助期间难以对其进行分析。一种基于黑色素的新过程，通过捕获辐射来利用能量；我们为针对黑色素的新黑色素瘤疗法奠定了基础，该疗法现已进入临床试验阶段； 黑色素可以屏蔽辐射，并提供了一种通过固态核磁共振分析研究黑色素结构的新方法；我们发现了真菌中的细胞外囊泡运输（与真菌“黑素体”的形成有关）。我们将在先前资助的成果和工具的基础上，研究人类致病真菌新型隐球菌的黑化作用，这种真菌每年导致全世界近一百万例脑膜炎病例，主要发生在艾滋病患者身上。为了关注真菌黑素体和黑化过程，提出了三个具体目标：1）为黑化囊泡群体中的货物生成分子定义；2）研究真菌黑素体与黑素体相互作用的机制。细胞壁；3) 研究新型隐球菌黑色素在其细胞壁支架上的分子结构，其对于毒力至关重要。也是治疗药物开发的潜在目标，针对黑色素的药物很有吸引力，因为它们可以用于对抗多种致病真菌。