MOLECULAR BASIS OF PHENOTYPIC SWITCHING IN 24067 MUTANT

我的研究项目的目标是更好地了解在新生隐球菌表型转换的分子机制。 有证据表明，表型转换是一种手段，这种真菌逃脱根除的主机和持久性的结果。 我将研究实验室菌株24067的一个变种，它在“光滑”和“起皱”表型之间高频切换。 除了改变的细胞表面之外，“褶皱”表型还表现出更大的包膜、丝状生长和增加的体内持久性。因此，这种转换产生了复杂的表型。 转变为“皱纹”表型似乎涉及与该病原体毒力相关的基因的上调。 此外，开关与两条染色体的长度变化有关。有待检验的假设是，染色体重排导致一个中心调节因子的差异表达，该调节因子进而调节与毒力相关的基因。我的项目的第一部分将涉及复杂表型的形态学研究。 第二部分旨在克隆介导这种复杂表型的基因，第三部分旨在确定染色体重排和转换之间是否存在因果关系。

The goal of my research project is to better understand the molecular mechanism underlying phenotypic switching in Cryptococcus neoformans. There is evidence that phenotypic switching is a means by which this fungus escapes eradication by the host and results in persistence. I will study a variant of the laboratory strain 24067 that switches at high frequency between a "smooth" and "wrinkled" phenotype. In addition to an altered cell surface the "wrinkled" phenotype exhibits a bigger capsule, filamentous growth and an increased in vivo persistence. Thus the switch yields a complex phenotype. The switch to a "wrinkle" phenotype appears to involve the upregulation of genes that are associated with virulence in this pathogen. In addition the switch is associated with a length change of two chromosomes. The hypothesis to be tested is that chromosomal rearrangement results in differential expression of a central regulator, which in turn regulates genes, which are associated with virulence. The first part of my project will involve morphological studies of the complex phenotype. The second part is designed to clone the gene mediating this complex phenotype and the third part will aim to establish whether there is a causative relationship between chromosomal rearrangement and switching.