Molecular Genetics of Aspergillosis

曲霉病的分子遗传学

基本信息

批准号：
6885329
负责人：
GREGORY S. MAY
金额：
$ 26.25万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2007-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Invasive pulmonary aspergillosis (IPA) is a fungal disease with high morbidity and mortality. Immunocompromised patients are at the greatest risk. The genetic program used by Aspergillus spp. during invasive growth is unknown, but its elucidation is critical to developing novel antifungal therapies. Work with A. fumigatus, the primary cause of aspergillosis, is hampered by the absence of critical molecular and genetic tools that would facilitate studies of gene regulation, gene function and a gene's role in pathogenesis. For this reason, part of this proposal is to develop the basic tools needed to advance the study of gene activity and function in A. fumigatus. We are developing molecular tools and auxotrophic mutants in the A. fumigatus strain AF293 to facilitate our investigations. In conjunction with the development of auxotrophic mutants, we will develop a set of transformation and expression vectors based on the different nutritional markers. We have performed preliminary suppression subtractive hybridization (SSH) experiments to identify genes that have increased expression during invasive growth. We will test the hypothesis that genes whose expression increases during invasive growth contribute to the progression of IPA. Using SSH and a murine model of IPA, we will identify those fungal genes that are highly expressed during invasive growth. We will use the A. fumigatus genome data being generated from the public sequencing project to establish the function of genes identified through SSH and in time explore the regulation of these genes and determine the signals that control their expression. These studies will provide us with a snapshot of the genetic program used by the fungus to grow in this unusual physiological state, leading to novel therapeutic approaches to managing IPA.

描述（由申请人提供）：侵袭性肺曲霉病（IPA）是一种发病率和死亡率较高的真菌病。免疫功能低下的患者面临的风险最大。曲霉菌属使用的遗传程序。侵袭性生长过程中的真菌感染尚不清楚，但其阐明对于开发新型抗真菌疗法至关重要。由于缺乏关键的分子和遗传工具来促进基因调控、基因功能和基因在发病机制中的作用的研究，烟曲霉（曲霉菌病的主要原因）的研究受到阻碍。因此，该提案的一部分是开发推进烟曲霉基因活性和功能研究所需的基本工具。我们正在开发烟曲霉菌株 AF293 的分子工具和营养缺陷型突变体，以促进我们的研究。结合营养缺陷型突变体的开发，我们将开发一套基于不同营养标记的转化和表达载体。我们进行了初步抑制消减杂交（SSH）实验，以确定在侵入性生长期间表达增加的基因。我们将检验以下假设：在侵袭性生长过程中表达增加的基因有助于 IPA 的进展。使用 SSH 和 IPA 小鼠模型，我们将识别那些在侵入性生长过程中高度表达的真菌基因。我们将利用公共测序项目产生的烟曲霉基因组数据来建立通过SSH鉴定的基因的功能，并及时探索这些基因的调控并确定控制其表达的信号。这些研究将为我们提供真菌在这种不寻常的生理状态下生长所使用的遗传程序的快照，从而产生管理 IPA 的新治疗方法。