Abstract
摘要:近年來,白色念珠球菌已成為院內感染最常見且最重要的致病菌之一。 然而在臨床上,可選擇的抗真菌藥物不多與具抗藥性真菌數量增加,造成治療上的困難。 因此,開發新的藥物與治療方式是一急迫且重要的議題。 光動力殺菌 (Antimicrobial photodynamic inactivation) 可經由結合光感物質 (Photosensitizer) 及特定波長照射光反應後,進一步產生活性氧分子而毒殺細胞。光動力治療 (Photodynamic therapy, PDT) 毒殺癌細胞已是臨床上許可的治療方式。然而,光動力殺菌仍多處於研究階段。 本計畫希望藉由了解光動力殺菌造成白色念珠球菌死亡的機制,替開發光動力治療真菌感染奠定基礎與未來應用的可行性。因此,本計畫研究目標一將利用白色念珠球菌轉錄因子的mutant library與DNA微陣列分析去了解白色念珠球菌對光動力殺菌的反應分子機制。 有趣的是,光動力殺菌後,加入幾丁聚醣 (Chitosan) 能產生協同 (synergistic) 殺菌效果。 然而,幾丁聚醣如何與光動力殺菌產生協同效果,仍不清楚。 因此,研究目標二仍將透過轉錄因子的mutant library與DNA微陣列分析,進一步了解幾丁聚醣與光動力殺菌協同毒殺白色念珠菌的分子機制。 為了了解光動力殺菌與幾丁聚醣對白色念珠球菌的協同效果能夠在動物模式看見療效,研究目標三將以皮膚、黏膜與血液三種感染模式進行光動力與幾丁聚醣治療,並評估其成效。 除了白色念珠球菌外,因醫療進步、人口老化與免疫不全病人增加,致病真菌感染人類的情況日益嚴重。 因此,本研究目標四將利用前述建立的技術與配方,評估此方式對其它人類致病真菌毒殺的效果。 這些研究成果不僅僅能了解白色念珠球菌對光動力與幾丁聚醣的反應機制,更能提供未來進行結合治療與製程配方開發更進一步的改良方式。
Abstract: Candida albicans has become the most predominant fungal species which is responsible for half of all clinical infections among human infectious fungal diseases. However, due to the limited choices of antifungal drugs and the emergence of drug-resistant strains, it has caused huge impact in the management of this infection. Thus, development or searching new drugs or alternative therapeutic methods to control fungal infections is urgent and required. Antimicrobial photodynamic inactivation (PDI) is a treatment that needs a nontoxic photosensitizer and visible light to trigger a reaction leading to generate reactive oxygen species (ROS). Although photodynamic therapy (PDT) has approved to treat cancer diseases in clinical, PDI therapy against microorganisms remains under study. This proposal will therefore to investigate mechanisms as to how C. albicans responds to PDI in that it will further provide useful guidelines for us to set a therapeutic paradigm for fungal infections and evaluate the feasibility for PDI applications in the future. Thus, my experiments outlined in Specific Aim 1 will use mutant library screening and transcriptome analysis to determine the mechanistic actions of C. albicans during the response to PDI. Interestingly, treatment of the exogenous chitosan after PDI causes a synergistic effect and exaggerates the effectiveness of PDI against C. albicans. Hence, Specific Aim 2 will therefore investigate how PDI-chitosan can drive a synergistic effect against C. albicans and what factors and genetic expressions are responsible for the susceptibility to PDI-chitosan treatment. To understand if the synergistic effect observed in vitro can be applied to in vivo, Specific Aim 3 will access the therapeutic feasibility of PDI-chitosan treatment against C. albicans by using cutaneous, mucosal and bloodstream infection models. Given that the medical advances and the increases of aging in populations and immunocompromised patients, emergence of fungal infectious diseases have rapidly increased. Therefore, Specific Aim 4 will evaluate the effectiveness of antifungal activity for several human fungal pathogens after PDI-chitosan treatment. Taken together, these studies will allow us to clarify the responding mechanisms of C. albicans to PDI, chitosan and PDI-chitosan in which it will provide useful information for further therapeutic development in order to control fungal infectious diseases.
Keyword(s)
白色念珠球菌
光動力殺菌
光感物質
幾丁聚醣
協同作用
Candida albicans
antimicrobial photodynamic inactivation
photosensitizer
chitosan
synergistic effect