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Genomic Research Capacity Building for Cryptococcosis Translational Studies

隐球菌病转化研究的基因组研究能力建设

基本信息

批准号：
10653960
负责人：
Joel Bazira
金额：
$ 55.26万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653960
关键词：
AIDS-Related Opportunistic Infections Acquired Immunodeficiency Syndrome Acute Adult Affect Africa African Alleles Basic Science Biological Assay Biological Markers Biology Brain CD4 Positive T Lymphocytes Caring Cause of Death Cerebrospinal Fluid Cessation of life Chromosomes Clinical Clinical Research Collaborations Communicable Diseases Complex Cryptococcal Meningitis Cryptococcosis Cryptococcus Development Diagnostic Diagnostic tests Disease Exhibits Failure Foundations Funding Genes Genetic Genetic Variation Genomics Genotype Goals Helper-Inducer T-Lymphocyte Hospitalization Human Immune Immune response Immunity Immunologic Markers Immunologics Immunology Impairment Infection Inflammatory Infrastructure Interleukin-2 Laboratories Mediating Medical Meningitis Minnesota Molecular Morbidity - disease rate Mycoses Neurocognitive Deficit Neurologic Neurological outcome Outcome Patient Isolation Patient-Focused Outcomes Patients Phenotype Plasma Process Research Research Personnel Risk Factors Science Serum Single Nucleotide Polymorphism Technology Th1 Cells Translating Translational Research Tuberculosis Uganda United States National Institutes of Health Universities Variant Virulence chemokine clinical infrastructure clinical practice clinical sequencing cytokine fungal genetics genome wide association study genomic biomarker high risk high risk population in silico knowledge base monocyte mortality mortality risk mouse model nervous system disorder neutrophil novel polarized cell programs public health relevance research study response routine care trait translational study treatment strategy

项目摘要

Abstract Cryptococcal meningitis (CM) is among the leading causes of death in AIDS-related opportunistic infections and causes 15% of AIDS-related mortality globally. In Uganda, CM accounts for 60% of adult meningitis in hospitalized patients. Even with treatment, the current mortality rate for CM is 65%, with surviving patients often exhibiting neurological impairment. This poor survival is due to a complex interaction between 1) failure to control fungal replication and 2) deleterious host immune response. To reduce CM deaths, we must simultaneously mitigate Cryptococcus virulence while rebalancing detrimental host responses towards protective immunity. The long-term objective of our research team is to identify novel treatment strategies for CM that reduce morbidity and mortality associated with this devastating disease. Our University of Minnesota, Mbarara University of Science and Technology, and Makerere University research team has collaborated on CM clinical studies since 2009 – including three NIH-funded trials. While similar clinical infrastructures are now present throughout Africa, there is still limited ability to perform associated basic and translational research related to CM. Thus, we will continue to build the infrastructure, knowledge base, and human capacity among African investigators to perform basic research in genomics and immunology that is translatable to clinical practice. Our research group has made two key discoveries that influence patient mortality with CM: a) an immune signature associated with patient mortality, and b) that Cryptococcus genotype affects both patient mortality and immune response. Specifically, our preliminary genome-wide association studies (GWAS) identified 38 Cryptococcus genes associated with immune response and patient mortality in closely related Ugandan CM patient isolates. Thus, the scientific objective for this proposal is to define the impact of these Cryptococcus biomarkers on the immune response, and validate a subset of the biomarkers in a mouse model of cryptococcosis. Two specific aims will accomplish this goal. In the first aim, we will identify genomic differences and biomarkers in Cryptococcus isolates that influence patient mortality and neurocognitive deficits after CM that encompass the genetic diversity present in Uganda. We will then analyze associations between these genetic differences and patient immune responses in the second aim to define both fungal genetic and human immune biomarkers that can be used in clinical practice as the first step towards development of a diagnostic bioassay. Taken together, these translational studies will define the molecular processes underlying CM and translate this information (i.e. biomarkers) into novel clinical assays to identify high-risk individuals for acute mortality or neurological impairment who would benefit from tailored medical care.

抽象的隐球菌性脑膜炎 (CM) 是艾滋病相关机会性死亡的主要原因之一感染并导致全球 15% 的艾滋病相关死亡。在乌干达，CM 占成人的 60% 住院患者的脑膜炎。即使进行治疗，目前 CM 的死亡率仍为 65%，幸存的患者经常表现出神经功能障碍。这种不良的生存是由于复杂的 1) 未能控制真菌复制和 2) 有害的宿主免疫反应之间的相互作用。到减少 CM 死亡，我们必须在重新平衡的同时减轻隐球菌毒力宿主对保护性免疫的有害反应。我们研究团队的长期目标的目的是确定新的 CM 治疗策略，以降低与此相关的发病率和死亡率毁灭性的疾病。我们的明尼苏达大学、姆巴拉拉科技大学，以及麦克雷雷大学研究团队自 2009 年以来一直在 CM 临床研究方面进行合作，其中包括三项 NIH 资助的试验。虽然类似的临床基础设施现在遍布非洲，但仍然存在进行与 CM 相关的基础和转化研究的能力有限。这样，我们将继续建设非洲调查人员的基础设施、知识库和人员能力进行可转化为临床实践的基因组学和免疫学基础研究。我们的研究小组取得了两项影响 CM 患者死亡率的关键发现：a) 免疫特征与患者死亡率相关，b) 隐球菌基因型影响两者患者死亡率和免疫反应。具体来说，我们初步的全基因组关联研究 (GWAS) 鉴定了 38 个与免疫反应和患者死亡率相关的隐球菌基因密切相关的乌干达 CM 患者分离株。因此，该提案的科学目标是定义这些隐球菌生物标志物对免疫反应的影响，并验证了其中的一个子集隐球菌病小鼠模型中的生物标志物。两个具体目标将实现这一目标。在第一个目标，我们将确定影响患者的隐球菌分离株的基因组差异和生物标志物 CM 后的死亡率和神经认知缺陷涵盖了乌干达存在的遗传多样性。然后我们将分析这些遗传差异与患者免疫反应之间的关联第二个目标是定义可用于临床的真菌遗传和人类免疫生物标志物实践是开发诊断生物测定的第一步。综合起来，这些转化研究将定义 CM 的分子过程并转化这些信息（即生物标志物）进入新的临床测定中，以识别急性死亡的高风险个体或神经障碍患者将受益于量身定制的医疗护理。