ISOLATION OF TARGETS FOR ANTIFUNGAL DRUGS IN C. ALBICANS

白色念珠菌是一种重要的人类病原菌，是外科手术患者、婴儿、糖尿病患者和免疫缺陷患者侵袭性真菌病的主要原因。尽管使用细胞抑制药物治疗，系统性念珠菌感染的死亡率接近30%。新药开发的一个主要障碍是难以为药物设计确定合适的目标。念珠菌的生物学排除了使用经典的遗传学方法来识别目标基因的可能性。在这一阶段的应用中，我们建议应用新的方法来抑制念珠菌的基因功能。首先，我们将应用一种我们在哺乳动物细胞中成功使用的方法：通过反义RNA的表达来抑制基因的功能。我们还建议评估一种新出现的产生功能丧失表型的方法的实用性：双链RNA的表达。这一阶段应用的目标是证明通过用反义RNA或双链RNA去除基因功能在念珠菌中进行遗传筛选的可行性。拟议的商业应用：在白色念珠菌中确定合适的药物设计靶点的能力将产生两个潜在的商业化途径。首先，可以在企业合作伙伴的帮助下，将目标部署为药物发现候选对象。其次，这里描述的技术方法可以与一个或多个公司合作伙伴协作应用。

Candida albicans is an important human pathogen that is the leading cause of invasive fungal disease in surgical patients, infants, diabetics and immunocomprimised individuals. Despite treatment with cytostatic drugs, the rate of mortality from systemic Candida infections approaches 30%. A major impediment to the development of new drugs is the difficulty of identifying suitable targets for drug design. The biology of Candida precludes the use of a classical genetic approach to identify target genes. In this phase application, we propose to apply novel approaches to inhibit gene function in Candida. First, we will apply an approach that we have employed successfully in mammalian cells: to inhibit the function of genes by the expression of antisense RNA. We also propose to assess the utility of a newly emerging method for creating loss-of-function phenotypes: the expression of double-stranded RNA. The goal of this phase I application is to demonstrate the feasibility of performing genetic screens in Candida by ablating gene function with antisense RNA or with double-stranded RNA. PROPOSED COMMERCIAL APPLICATION: The ability to identify suitable targets for drug design in Candida albicans will yield two potential avenues for commercialization. First, the targets can be deployed as drug-discovery candidates with the help of corporate partners. Second, the technical approaches described herein may be applied in collaboration with one or more corporate partners.