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.

项目概要/摘要 毛霉菌病是一种致命的侵袭性感染，由属于该亚门的几种真菌生物体引起 毛霉亚门，毛霉目。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、实体器官或 骨髓移植、中性粒细胞减少症、创伤和烧伤（例如伊拉克和阿富汗的受伤士兵）， 接受血液透析患者的恶性血液疾病和去铁胺治疗。这 感染通常是通过吸入自然界中普遍存在的孢子而获得的，并导致犀牛- 眼眶疾病（几乎仅发生在 DKA 患者中）或肺部疾病（主要发生在中性粒细胞减少性白血病患者中）。 毛霉菌病的治疗选择有限。目前没有疫苗，只有两种抗真菌药物 美国FDA批准用于治疗这种疾病的药物。第一种是两性霉素 B (AmB)，它具有严重的 不良反应，包括肾毒性，并且临床成功非常有限。艾沙康唑最近 批准用于治疗毛霉菌病，但并不优于 AmB 治疗。在没有手术切除的情况下 感染病灶（如鼻脑毛霉菌病患者的眼睛切除）、抗真菌治疗 单独治疗很少有疗效。即使手术清创与大剂量抗真菌治疗相结合， 与毛霉菌病相关的死亡率>50%。对于长期中性粒细胞减少症或播散性中性粒细胞减少症的患者 疾病死亡率为90-100%。此外，由于联邦没有要求报告真菌感染， 毛霉菌病的真实患病率可能比目前报道的要高得多。高得令人难以接受 死亡率、有限的治疗选择以及严重毁容手术治疗的极高发病率使得 寻找治疗和预防毛霉菌病的替代策略势在必行。我们最近发表的作品 表明毛霉目物种与宿主细胞受体结合，以便通过血管侵入宿主组织 内皮细胞和肺上皮细胞。在目标 1 中，我们将探索阻断 毛霉目真菌与宿主细胞受体之间的相互作用。目标 2 将侧重于识别和表征 真菌编码的药物靶点，旨在验证新的、迫切需要的抗真菌药物的其他靶点 真菌疗法。这里提出的工作的最终目标是开发新的抗真菌策略 杀死真菌或破坏对肺部疾病进展很重要的分子相互作用 毛霉菌病。