Genetics of susceptibility to candidiasis

描述（由申请人提供）：本申请对先前资助的项目R21DE019414 - 01进行竞争性修订，是对NOT-OD-09 - 058 "NIH宣布恢复法案资金可用于竞争性修订申请"的回应。 白色念珠菌引起粘膜和播散性疾病。口咽念珠菌病（OPC）在许多患者中导致显著的发病率，特别是那些患有HIV/AIDS的患者。血源性播散性念珠菌病（HDC）是一种医疗保健相关疾病，即使使用当前的抗真菌治疗，也会导致30 - 50%的死亡率。虽然OPC和HDC发展的临床风险因素是明确定义的，但只有少数处于这些疾病风险中的患者实际上会发展它们。对OPC和HDC易感性的另一个重要决定因素是控制宿主对白色念珠菌反应的关键基因中存在多态性。该项目的总体目标是使用近交系小鼠来识别这些基因。这些信息有望为宿主防御OPC和HDC的机制提供新的见解，并提供新的遗传方法来识别患有这些疾病的风险特别高的患者。 我们已经测试了17个近交系小鼠品系对OPC和HDC的敏感性。我们发现不同的菌株对这两种疾病的易感性有显着差异。接下来，我们使用计算单倍型作图来确定基因组区域-数量性状位点（QTL）-可能包含的基因的变化是负责这些菌株之间的疾病易感性差异。该分析的结果确定了78个和176个基因，其中多态性可能与OPC和HDC的易感性相关。然而，单倍型作图的局限性是假阳性结果频繁。因此，需要额外的方法来确定QTL中的哪些基因实际上影响对这些疾病的易感性。 在这个竞争性的修订，我们建议使用微阵列分析，以确定宿主基因的表达水平在口腔组织的不同品系的小鼠，不同的敏感性OPC。我们计划使用来自不同品系小鼠肾脏的RNA进行类似的分析，这些小鼠对HDC的敏感性不同（肾脏是HDC小鼠的靶器官）。将分析这些微阵列数据以确定通过单倍型作图鉴定的哪些基因：1）在靶器官中表达，和2）在易感小鼠品系与抗性小鼠品系中具有不同的表达水平。这些数据将使我们能够优先考虑疾病易感基因，以便进一步深入研究。它们也将是了解宿主对OPC和HDC的反应以及识别这些疾病的潜在生物标志物的极好资源。 公共卫生相关性：这项研究与公共卫生高度相关，因为口咽念珠菌病是艾滋病毒/艾滋病患者的一个重要问题，特别是那些没有接受高效抗逆转录病毒治疗的患者。此外，血源性播散性念珠菌病在住院患者中很常见，即使经过治疗，仍然会导致显著的死亡率。发现控制口咽和播散性念珠菌病易感性的宿主基因有望为宿主防御这些疾病的机制提供新的见解，并提供新的遗传方法来识别患有这些疾病的风险特别高的患者。此外，这一补充将使洛杉矶生物医学研究所、杜克大学和斯坦福大学的科学家和技术人员能够为这一项目投入更多的时间，从而促进他们继续充分就业。

DESCRIPTION (provided by applicant): This application for a Competitive Revision to the previously funded project, R21DE019414-01 is in response to NOT-OD-09-058 "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications". Candida albicans causes both mucosal and disseminated disease. Oropharyngeal candidiasis (OPC) results in significant morbidity in many patients, especially those with HIV/AIDS. Hematogenously disseminated candidiasis (HDC) is a healthcare-associated disease that results in 30 to 50% mortality, even with current antifungal therapy. Although the clinical risk factors for development of OPC and HDC are well-defined, only a minority of patients who are at risk for either of these diseases actually develop them. An additional important determinant of susceptibility to OPC and HDC is the presence of polymorphisms in key genes that govern the host response to Candida albicans. The overall goal of this project is to use inbred strains of mice to identify these genes. This information holds promise to provide new insight into mechanisms of host defense against OPC and HDC, as well as to provide new genetic approaches to identify patients who are at particularly high risk of developing these diseases. We have already tested the susceptibility of 17 inbred mouse strains to OPC and HDC. We found that different strains had significantly different susceptibility to both diseases. Next, we used computational haplotype mapping to identify genomic regions--quantitative trait loci (QTLs)--that may contain genes whose variations are responsible for these strain-to-strain differences in disease susceptibility. The results of this analysis identified 78 and 176 genes in which polymorphisms may be associated with susceptibility to OPC and HDC, respectively. However, a limitation of haplotype mapping is that false positive results are frequent. Therefore additional methods are required to determine which of the genes in the QTLs actually influence susceptibility to these diseases. In this competitive revision, we propose to use microarray analysis to determine host gene expression levels in the oral tissues of different strains of mice that differ in their susceptibility to OPC. We plan to perform a similar analysis using RNA from the kidneys of different strains of mice that differ in susceptible to HDC (The kidney is the target organ in mice with HDC). These microarray data will be analyzed to determine which of the genes identified by haplotype mapping are: 1) expressed in the target organs, and 2) have different levels of expression in susceptible vs. resistant mouse strains. These data will enable us to prioritize disease susceptibility genes for further in-depth study. They will also be an excellent resource for understanding the host response to OPC and HDC, as well as for identifying potential biomarkers for these diseases. PUBLIC HEALTH RELEVANCE: This research is highly relevant to public health because oropharyngeal candidiasis is a significant problem in patients with HIV/AIDS, especially those who are not receiving highly active antiretroviral therapy. Also, hematogenously disseminated candidiasis is common in hospitalized patients and still causes significant mortality, even with treatment. Discovering host genes that govern susceptibility to oropharyngeal and disseminated candidiasis holds promise to provide new insight into mechanisms of host defense against these diseases, as well as to provide new genetic approaches to identify patients who are at particularly high risk of developing these diseases. In addition, this supplement will enable scientists and technicians at Los Angeles Biomedical Research Institute, Duke University, and Stanford University to devote significantly more time to this project, and thereby facilitate their continued full employment.