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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

基本信息

批准号：
9814832
负责人：
Vincent Michael Bruno
金额：
$ 52.8万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
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/9814832
关键词：
Acidosis Adopted Adrenal Cortex Hormones Adverse effects Afghanistan Alveolar 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 Cells Epithelium Excision Eye FDA approved Fungal Components Fungal Genes Gefitinib Gene Expression Gene Expression Profile Genes Genetic screening method 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 Soldier Solid Therapeutic Tissues Trauma Treatment Protocols Up-Regulation Vaccines Vascular Endothelium Virulence Work clinically relevant combinatorial comparative genomics experimental study fungus gene product glucosidase holistic approach improved in vivo inhibitor/antagonist 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

项目摘要

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.

项目总结/文摘