Therapeutic targeting of growth factor receptors to treat Mucormycosis

生长因子受体的治疗靶向治疗毛霉菌病

• 批准号: 10409703
• 负责人: Vincent Michael Bruno
• 金额: $ 49.24万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409703
• 关键词: Acidosis; Adopted; Adrenal Cortex Hormones; Adverse effects; Afghanistan; Amphotericin B; Animal Model; Antifungal Agents; Antifungal Therapy; Attenuated; Binding; Bone Marrow Transplantation; Burn injury; CRISPR/Cas technology; Caring; Cell Wall; Cerebrum; Clinical; Data; Debridement; Deferoxamine; Development; Diabetes Mellitus; Disease; Disease Progression; Dose; Drug Targeting; ERBB2 gene; Environment; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Excision; Eye; FDA approved; Fungal Components; Fungal Genes; Gefitinib; Gene Expression; Gene Expression Profile; Genes; Goals; Growth Factor Receptors; Hematologic Neoplasms; Hematological Disease; Homologous Gene; Hyperglycemia; In Vitro; Infection; Inhalation; Invaded; Iraq; Lung; Malignant - descriptor; Malignant Neoplasms; Measures; Messenger RNA; Molecular; Morbidity - disease rate; Mucorales; Mucormycosis; Mycoses; National Institute of Allergy and Infectious Disease; Nature; Neutropenia; Operative Surgical Procedures; Organ; Organism; PDGFRB gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Prevalence; Publishing; RNA; RNA Interference; Receptor Activation; Receptor Cell; Receptor Protein-Tyrosine Kinases; Reporting; Reproduction spores; Research; Rhizopus; Risk Factors; Role; Salvage Therapy; Signal Pathway; Signal Transduction; Solid; Therapeutic; Tissues; Trauma; Treatment Protocols; Up-Regulation; Vaccines; Vascular Endothelium; Virulence; Work; alveolar epithelium; clinically relevant; combinatorial; comparative genomics; experimental study; fungus; gene product; genetic testing; glucosidase; holistic approach; improved; in vivo; inhibitor; leukemia; mortality; mouse model; nephrotoxicity; new therapeutic target; novel; novel therapeutics; pathogen; pathogenic microbe; posaconazole; prevent; success; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; treatment optimization; wounded soldier

PROJECT SUMMARY/ABSTRACT Mucormycosis is a deadly invasive infection caused by several fungal organisms belonging to the subphylum Mucormycotina, order Mucorales. The major risk factors include uncontrolled diabetes mellitus that results in hyperglycemia and ketoacidosis (DKA), other forms of acidosis, treatment with corticosteroids, solid organ or bone marrow transplantation, neutropenia, trauma and burns (e.g., wounded soldiers in Iraq and Afghanistan), malignant haematological disorders and deferoxamine therapy in patients receiving haemodialysis. The infection is generally acquired by inhalation of spores that are ubiquitous in nature and cause either rhino- orbital (almost exclusively in DKA patients) or pulmonary (mainly in neutropenic leukemic patients) disease. The treatment options for Mucormycosis are limited. There are currently no vaccines and only two antifungal agents approved by the USA FDA to treat this disease. The first is Amphotericin B (AmB) which has serious adverse effects, including nephrotoxicity, and very limited clinical success. Isavuconazole was recently approved to treat mucormycosis but it is not superior to AmB treatment. In the absence of surgical removal of the infected focus (such as excision of the eye in patients with rhinocerebral mucormycosis), antifungal therapy alone is rarely curative. Even when surgical debridement is combined with high-dose antifungal therapy, the mortality associated with mucormycosis is >50%. In patients with prolonged neutropenia or disseminated disease, mortality is 90-100%. Furthermore, since there are no federal requirements to report fungal infections, the true prevalence of mucormycosis is likely to be much higher than currently reported. The unacceptably high mortality rate, limited options for therapy and the extreme morbidity of highly disfiguring surgical therapy make it imperative to look for alternative strategies to treat and prevent mucormycosis. Our recently published work suggests that Mucorales species engage host cell receptors in order to invade host tissue through the vascular endothelium and the pulmonary epithelium. In Aim 1, we will explore the therapeutic potential of blocking the interaction between Mucorales fungi and host cell receptors. Aim 2 will focus on identifying and characterizing fungal-encoded drug targets with the goal of validating additional targets for novel, desperately needed anti- fungal therapies. The ultimate goal of the work proposed here is to develop novel antifungal strategies to either kill the fungus or disrupt molecular interactions that are important for disease progression of pulmonary mucormycosis.

项目摘要/摘要 粘膜细胞增多是由属于亚光的几种真菌生物引起的致命侵入性感染 粘液菌，粘膜。主要危险因素包括不受控制的糖尿病，导致 高血糖和酮症酸中毒（DKA），其他形式的酸中毒，皮质类固醇治疗，固体器官或 骨髓移植，中性粒细胞减少，创伤和烧伤（例如，伊拉克和阿富汗受伤的士兵）， 患有血液透析的患者的恶性血液学疾病和脱氧胺疗法。这 通常，通过吸入无处不在的孢子来获得感染，并引起犀牛 轨道（几乎完全在DKA患者中）或肺（主要是中性粒细胞性白血病患者）疾病。 粘膜细胞增多的治疗选择受到限制。目前没有疫苗，只有两种抗真菌 美国FDA批准的代理商治疗这种疾病。首先是两性霉素B（AMB） 不良反应，包括肾毒性和非常有限的临床成功。 Isavuconazole最近是 被批准用于治疗粘膜菌病，但不优于AMB治疗。在没有手术去除的情况下 受感染的焦点（例如鼻脑胶质细胞增多患者的眼睛切除），抗真菌疗法 一个人很少能治愈。即使将手术清创术与高剂量抗真菌疗法结合起来， 与粘膜细胞增多相关的死亡率> 50％。长时间中性粒细胞减少或分布的患者 疾病，死亡率为90-100％。此外，由于没有联邦要求报告真菌感染的要求 粘膜菌病的真正患病率可能比目前报道的要高得多。不可接受的高 死亡率，治疗方案有限以及高度毁容手术治疗的极端发病率使得 必须寻找治疗和预防肌肉菌病的替代策略。我们最近发表的作品 表明粘膜物种会吸引宿主细胞受体，以通过血管侵袭宿主组织 内皮和肺上皮。在AIM 1中，我们将探索阻止该的治疗潜力 粘膜真菌与宿主细胞受体之间的相互作用。 AIM 2将专注于识别和表征 真菌编码的药物靶标的目的是验证新颖，急需的反 - 真菌疗法。这里提出的工作的最终目标是制定新颖的抗真菌策略 杀死对肺部疾病进展至关重要的真菌或破坏分子相互作用 粘膜细胞增多。