According to the most recent CDC report, the incidence of sepsis in the United States is over 1.7 million each year, resulting in about 270,000 deaths and over $20 billion in healthcare costs. Sepsis results from infection of any microorganisms with bacteria being the most common. Pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharides (LPS) activate innate immune cells, macrophages in particular, as well as tissue resident cells such as vascular endothelial cells and cardiomyocytes through Toll-like receptors (TLRs). The activated macrophages engulf and kill the microbes. On the one hand, this process may reduce microbial load and limit the infection. On the other hand, these activated macrophages may elicit a stronger than desirable inflammatory response by secreting excess amounts of cytokines and oxidative molecules, acting on tissue resident cells and leading to tissue damage. Moreover, the damaged tissues release endogenous damage-associated molecular patterns (DAMPs), which further escalate the inflammatory cascade through binding to TLRs, particularly TLR2 and TLR4, on immune cells and tissue resident cells. This vicious cycle rapidly leads to multi-organ injury, and eventually death. The quick evolution and the complexity of the pathology of bacterial sepsis make it extremely difficult to treat. Current management still relies on source control, antibiotics, and organ support. Although inflammation plays a key detrimental role in the pathogenesis of septic shock, no anti-inflammatory approaches have been proved successful due to various reasons. In the past 10 years, we and collaborators 1) isolated a new single compound from Chinese herbs, determined its structure, and named it Sparstolonin B (SsnB); 2) characterized SsnB as a dual TLR2 and TLR4 antagonist; 3) discovered that SsnB antagonizes TLR2/4 by disrupting the interaction between TIRAP and MyD88, a unique key event in TLR2/4 signaling; 4) demonstrated that SsnB effectively inhibits inflammatory responses of multiple cell lines and primary cell types to both exogenous and endogenous TLR2/4 ligands; 5) showed that SsnB inhibits the hypoxia-induced cardiomyocyte inflammatory response and apoptosis in cell culture and in live heart slices; 6) reported that intraperitoneal administration of SsnB effectively reduced the death of LPS endotoxemic mice; and 7) in most recent preliminary study demonstrated that SsnB prolonged survival of male CD-1 mice using a cecal ligation and puncture (CLP) model. On the basis on these achievements, we are in a unique position to develop SsnB as a novel therapy for bacterial sepsis. Toward this goal, we propose in this STTR phase I project to establish the feasibility of clinical development. We propose two specific aims: SA1. To establish the effectiveness of SsnB in various mouse strains using the CLP model of bacterial sepsis; and SA2. To optimize the therapeutic regimen of SsnB to treat CLP-induced sepsis. We believe this safe and effective natural compound has the potential to reduce the mortality of bacterial sepsis and reduce healthcare and related costs tremendously. Public Health Relevance Statement NARRATIVE: Bacterial sepsis is a devastating condition that results in high mortality and huge healthcare cost. In the past 10 years, we discovered and mechanistically characterized a Chinese herb-derived compound, Sparstolonin B that selectively antagonize toll-like receptors 2 and 4 signaling. We propose in this STTR phase I project to establish the feasibility of clinical development of Sparstolonin B as a novel therapy for bacterial sepsis.
Project Terms: Achievement ; Achievement Attainment ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Antibiotics ; Antibiotic Agents ; Antibiotic Drugs ; Miscellaneous Antibiotic ; Bacteria ; Cell Culture Techniques ; cell culture ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cells ; Cell Body ; Centers for Disease Control and Prevention (U.S.) ; CDC ; Centers for Disease Control ; Centers for Disease Control and Prevention ; United States Centers for Disease Control ; United States Centers for Disease Control and Prevention ; Clinical Trials ; Cessation of life ; Death ; Epithelial Cells ; Evolution ; Goals ; Heart ; HMGB1 Protein ; Amphoterin ; Chromosomal Protein, Nonhistone, HMG1 ; FM1 Gene Product ; HMG-1 ; HMG-1 Protein ; HMG1 ; HMG3 ; Heparin-Binding Protein p30 ; High Mobility Group Box Protein 1 ; High Mobility Group Protein 1 ; High-Mobility Group (Nonhistone Chromosomal) Protein 1 ; High-Mobility Group Box 1 ; Nonhistone Chromosomal Protein HGM1 ; SBP-1 ; Sulfoglucuronyl Carbohydrate Binding Protein ; Hospitals ; Incidence ; Infection ; Inflammation ; Kidney ; Kidney Urinary System ; renal ; Laboratories ; Ligands ; Lipopolysaccharides ; Lipoproteins ; Lung ; Lung Respiratory System ; pulmonary ; macrophage ; MÏ ; male ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Names ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Nitric Oxide ; Endogenous Nitrate Vasodilator ; Endothelium-Derived Nitric Oxide ; Mononitrogen Monoxide ; Nitrogen Monoxide ; Nitrogen Protoxide ; endothelial cell derived relaxing factor ; Pathology ; Patients ; Physicians ; Play ; Role ; social role ; Safety ; Septic Shock ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Tissues ; Body Tissues ; United States ; cytokine ; Health Care Costs ; Health Costs ; Healthcare Costs ; Healthcare ; health care ; Apoptosis ; Apoptosis Pathway ; Programmed Cell Death ; Investigational New Drug Application ; Organ ; Phase ; Cardiac Myocytes ; Cardiac Muscle Cells ; Cardiocyte ; Heart Muscle Cells ; Heart myocyte ; cardiomyocyte ; Hepatocyte ; Hepatic Cells ; Hepatic Parenchymal Cell ; Liver Cells ; Failure ; Hypoxia ; Hypoxic ; Oxygen Deficiency ; Research Project Grants ; R-Series Research Projects ; R01 Mechanism ; R01 Program ; Research Grants ; Research Projects ; Therapeutic ; Tubular ; Tubular formation ; Inflammatory ; Immunes ; Immune ; Event ; intraperitoneal ; microorganism ; Source ; cell type ; Pattern ; multiorgan injury ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; microbial ; TLR protein ; Toll-Like Receptor Family Gene ; Toll-like receptors ; Structure ; novel ; Pathogenesis ; Reporting ; Position ; Positioning Attribute ; Modeling ; Cardiac Muscle Myosins ; Cardiac Myosins ; chinese herbal ; Chinese Herbs ; Leiomyocyte ; Smooth Muscle Cells ; Smooth Muscle Tissue Cell ; Smooth Muscle Myocytes ; Inflammatory Response ; Molecular Interaction ; Binding ; Vascular Endothelial Cell ; Effectiveness ; small molecule ; TIL4 ; TLR2 ; TLR2 receptor ; Toll-Like Receptor 2 ; Toll/Interleukin 1 Receptor-Like 4 ; Toll/Interleukin 1 Receptor-Like 4 Gene ; Toll/Interleukin 1 Receptor-Like Protein 4 ; TLR2 gene ; Homolog of Drosophila TOLL ; TLR4 ; Toll Homologue ; toll-like receptor 4 ; TLR4 gene ; Alveolar ; Bacterial Model ; Mouse Strains ; Slice ; Small Business Technology Transfer Research ; STTR ; Molecular ; Process ; cost ; Sepsis ; blood infection ; bloodstream infection ; pathogen ; Microbe ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; Regimen ; HepG2 ; Hep G2 ; HepG2 cell line ; TIRAP gene ; Mal gene ; MyD88 adapter-like ; TIRAP ; toll-interleukin 1 receptor (TIR) domain containing adaptor protein ; clinical development ; cecal ligation puncture ; CLP model ; CLP mouse model ; Cecal ligation perforation ; pharmacokinetics and pharmacodynamics ; PK/PD ; systemic inflammatory response ; systemic inflammation ; organ injury ; injury to organs ;
