CANDIDACIDAL MECHANISMS OF SALIVARY HISTATINS

唾液组氨酸的抗念珠菌机制

• 批准号: 7425420
• 负责人: Mira Edgerton
• 金额: $ 31.27万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-03-01 至 2009-07-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425420
• 关键词: ATPase Domain; Acquired Immunodeficiency Syndrome; Amino Acids; Antifungal Agents; Azole resistance; Azoles; Binding; Binding Sites; Biological Assay; Candida; Candida albicans; Candidiasis; Carrier Proteins; Cell Cycle; Cell Cycle Arrest; Cell Surface Receptors; Cell Wall; Cell membrane; Cells; Chemotherapy-Oncologic Procedure; Class; Complex; Condition; Coupled; Development; Disruption; Drug resistance; Event; Family; Family member; Future; Genes; Genome; Global Change; Heat Stress Disorders; Heat-Shock Proteins 70; Homeostasis; Host Defense; Human; In Vitro; Industrial fungicide; Infection; Intracellular translocation; Ion Channel; Ions; Major salivary gland structure; Maps; Measures; Membrane; Microarray Analysis; N-terminal; Nature; Numbers; Oral; Other Finding; Pathway interactions; Patients; Physiological; Potassium Channel; Predisposition; Premature Infant; Principal Investigator; Process; Protein Overexpression; Proteins; Recurrence; Regulation; Regulator Genes; Resistance; Role; Salivary Glands; Sorting - Cell Movement; Specificity; Toxic effect; Transcript; Yeasts; base; cell envelope; crosslink; design; diabetic; fungus; head and neck cancer patient; histatin 5; histidine-rich proteins; human neutrophil peptide 1; improved; in vivo; killings; member; mutant; novel; oropharyngeal thrush; polypeptide; programs; response; salivary histatins

DESCRIPTION (provided by applicant): Oropharyngeal candidiasis caused by Candida albicans is prevalent in patients receiving cancer chemotherapy, AIDS patients, diabetics, or premature infants. Human salivary Histatin 5 (Hst 5) is a potent fungicidal protein that lacks toxicity to humans and has the ability to kill azole-resistant Candida strains. Our previous studies have demonstrated that Hst 5 exerts antifungal activity through a complex multi-mechanistic process. Toxic activity is initiated by binding to a C. albicans 70 kDa protein in the cell envelope that we have recently identified as Ssa1, a member of the HSP70 family involved in binding and transport of proteins across cell membranes. Following intracellular translocation, Hst 5 disrupts membrane ion gradients, perhaps through Trk1, resulting in disruption of volume regulation and G1 cell cycle arrest. However, many gaps remain in our understanding of this process. We do not know the critical requirements for Hst 5 binding with Ssa1 proteins. Delineation of the precise binding sites of Hst 5 with Ssa protein are crucial in design of antifungal toxic proteins targeted to the yeast cell surface receptors. In addition, we do not yet know the identity of yeast channels that participate in ion homeostasis disrupted by Hst 5, nor do we understand the global changes that occur ultimately leading to cell cycle arrest. To more fully understand these processes, we propose to 1) Identify the Hst 5 binding domain in Ssa1p in vitro 2) Assess the role of Ssa1/2p required for Hst 5 function in vivo, 3) Determine the role of the major yeast potassium channel, Trk1p, in Hst 5 killing and 4) Identify yeast gene transcripts, especially cell cycle regulatory genes, altered by Hst 5 using full genome C. albicans microarray analysis. An understanding of the mechanism of Hst 5-induced killing and the nature of its specificity for yeast cells over human cells will contribute to future development of improved antifungal drugs.

描述（由申请人提供）：由白色念珠菌引起的口咽念珠菌病在接受癌症化疗的患者、艾滋病患者、糖尿病患者或早产儿中普遍存在。人唾液组胺素5（Hst 5）是一种对人体无毒的有效杀真菌蛋白，具有杀死唑类耐药念珠菌菌株的能力。我们以前的研究表明，Hst 5通过一个复杂的多机制的过程发挥抗真菌活性。毒性活性是通过与C.白色念珠菌细胞膜中的70 kDa蛋白，我们最近鉴定为Ssa 1，它是HSP 70家族的一员，参与蛋白质的结合和跨细胞膜转运。在细胞内易位后，Hst 5可能通过Trk 1破坏膜离子梯度，导致体积调节和G1期细胞周期停滞的破坏。然而，我们对这一进程的理解仍有许多差距。我们不知道Hst 5与Ssa 1蛋白结合的关键要求。Hst 5与Ssa蛋白的精确结合位点的确定对于设计靶向酵母细胞表面受体的抗真菌毒性蛋白至关重要。此外，我们还不知道参与Hst 5破坏的离子稳态的酵母通道的身份，我们也不了解最终导致细胞周期停滞的全局变化。为了更全面地理解这些过程，我们建议1）在体外鉴定Ssa 1 p中的Hst 5结合结构域2）评估Hst 5功能所需的Ssa 1/2 p在体内的作用3）确定主要的酵母钾通道Trk 1 p在Hst 5杀伤中的作用4）使用全基因组C鉴定Hst 5改变的酵母基因转录本，特别是细胞周期调控基因。白色念珠菌微阵列分析。了解Hst 5诱导的杀伤机制及其对酵母细胞的特异性将有助于未来开发改进的抗真菌药物。