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Transformed Probiotic Bacteria for Treatment of Chronic Diseases

用于治疗慢性疾病的转化益生菌

基本信息

批准号：
7431222
负责人：
SEAN Stephen DAVIES
金额：
$ 230.25万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7431222
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Acetates Active Sites Acute Acyl Carrier Protein Acyltransferase Adhesions Adjuvant Adult Adverse effects Affect Affinity Age Aldehydes Alkynes Amaze American Type Culture Collection Amines Amino Acid Sequence Amino Acids Anabolism Anaerobic Bacteria Angiotensin I Angiotensin II Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Antibiotics Antibodies Antigens Antioxidants Apolipoprotein A-I Arachidonic Acids Arterial Fatty Streak Ascorbic Acid Aspergillus Atherosclerosis Attenuated Autoantigens Automobile Driving Avidin Award Azides B-Cell Activation B-Lymphocytes Back Bacteria Bacteriophages Benign Bifidobacterium Binding Bioavailable Biochemistry Biological Biological Assay Biological Availability Biological Process Biology Bioreactors Biotechnology Biotin Bite Blood Blood Circulation Blood Glucose Blood Pressure Blood Vessels Bolus Infusion CD4 Positive T Lymphocytes CD80 Antigens Carbon Cardiovascular Diseases Caseins Caspase Cause of Death Cell Adhesion Molecules Cell surface Cells Cellular Membrane Cellular biology Cessation of life Characteristics Chemistry Cholesterol Chronic Chronic Disease Clinical Trials Code Codon Nucleotides Collaborations Complement Complex Condition Coronary heart disease Cosmids Cost Savings Coupled Creativeness Cues Culture Media Cultured Cells DNA DNA Sequence Daily Dependence Development Diabetes Mellitus Diet Digestion Disease Disease Progression Disease model Dose Drops Drug Compounding Drug Delivery Systems Drug Formulations Drug Prescriptions Drug usage Eating Economic Burden Economic Inflation Elderly Elements Encapsulated Endopeptidases Energy Intake Engineering Ensure Enterobacteriaceae Environment Enzyme Gene Enzyme Inhibition Enzymes Escherichia coli Essential Genes Event Evolution Excretory function F2-Isoprostanes Failure Family Fatty Acids Feces Feedback Fluorescence Food Food Additives Free Radicals Functional disorder Funding Gastrointestinal tract structure Generations Genes Genetic Genome Genomics Glucose Glycoproteins Green Fluorescent Proteins Growth Half-Life Health Benefit Healthcare Systems Hearing Helper-Inducer T-Lymphocyte High Density Lipoproteins Homeostasis Horizontal Gene Transfer Hormones Hour Human Hydro-Lyases Hydrogen Peroxide Hydroxymethylglutaryl-CoA Reductase Inhibitors Hydroxymethylglutaryl-CoA reductase Hypertension Hypoglycemia Hypotension Image Immune response Immunohistochemistry In Situ In Vitro Incubated Individual Inflammation Inflammatory Response Inherited Injection of therapeutic agent Injury Institutes Insulin Intervention Intestines Intraperitoneal Injections Invaded Ischemia Ischemic Preconditioning Isomerism Journals Keto Acids Ketones Kinetics Knock-out Knowledge LDL Cholesterol Lipoproteins Label Lactobacillus Lactobacillus acidophilus Lactobacillus casei Left Leptin Lesion Libraries Life Light Link Lipid Peroxidation Lipids Literature Liver Localized Location Longevity Longitudinal Studies Lovastatin Low Density Lipoprotein Receptor Low-Density Lipoproteins Lysine Mass Spectrum Analysis Measures Mediating Medical Metabolic Methods Methyltransferase Microbe Milk Mind Minor Mitomycin Modeling Moderate Exercise Modification Molds Molecular Biology Molecular Weight Monitor Mus Mutation NADPH Oxidase Nature Needles Nisin Numbers Obese Mice Obesity Oncogenes Oral Oral Administration Oxidative Stress Pathogenesis Pathology Pathway interactions Patients Peptide Hydrolases Peptide Signal Sequences Peptides Peptidyl-Dipeptidase A Performance Peroxidase Phage Display Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Physical condensation Physiological Physiological Processes Physiological reperfusion Pilot Projects Planet Mars Plasma Plasmids Polymerase Chain Reaction Population Probability Probiotics Procedures Process Production Productivity Proline Property Prostaglandin Receptor Prostaglandin-Endoperoxide Synthase Prostaglandins Protein Biosynthesis Protein Overexpression Proteins Proteolysis Purpose Pyridoxamine Pyruvaldehyde Quality Control Radioactivity Radiolabeled Range Rate Rattus Reaction Reactive Oxygen Species Reagent Recombinants Recruitment Activity Regulation Reperfusion Injury Reperfusion Therapy Reporting Research Personnel Research Project Grants Resistance Resources Rest Risk Risk Factors Role Route Safety Schedule Science Screening procedure Series Serum Serum Albumin Side Signal Transduction Signaling Molecule Site Solutions Solvents Sorting - Cell Movement Source Specific qualifier value Specificity Speed Standards of Weights and Measures Sterility Stream Stretching Structure Surface System T-Lymphocyte Techniques Technology Testing Therapeutic Therapeutic Effect Therapeutic Uses Thinking Thymidine Time Tissues Toxic effect Toxin Training Programs Translational Research Treatment Cost Treatment Efficacy United States Universities Unsaturated Fatty Acids Upper arm Variant Vascular Diseases Week Whole Organism Withdrawal Work absorption abstracting adduct analog antigen antibody binding antigen binding base carbonyl compound chemical synthesis commensal microbes controlled release cost cycloaddition cyclooxygenase 1 cyclooxygenase 2 cytotoxicity day design desire diabetic diaries direct application drug production drug synthesis enoyl reductase epimerization experience falls fatty acid oxidation field study gastrointestinal gene therapy human disease hypercholesterolemia improved in vivo innovation insight insulin secretion interest ketoaldehyde killings lipophilicity member microbial mimetics mouse model neutralizing antibody novel novel strategies oxidation oxidized lipid oxidized low density lipoprotein pathogenic bacteria peptide L peptide analog peptide synthase peroxidation physical property pill polyketide synthase pressure prevent promoter protein aminoacid sequence protein crosslink protein degradation protein expression protein function radiotracer research study response retiree size small molecule stoichiometry synthetic enzyme tetanus toxin fragment C therapeutic protein therapeutic target tissue/cell culture tool treatment duration trend vector vector vaccine wasting young adult

项目摘要

The continual increase in the number of patients suffering from chronic medical conditions that require long term treatment with therapeutic drugs such as hypercholesterolemia, hypertension, diabetes, and obesity has proven a tremendous economic burden, both to individuals and to health care systems. The traditional approach to drug production has been chemical synthesis of the needed compounds, then purification, formulation, and distribution. We propose to investigate a novel approach to long-term drug production and delivery: using probiotic intestinal bacteria transformed to express the required drug and inoculated into a patient for chronic colonization and therapeutic production. This approach essentially takes the notion of gene therapy and rather than altering the genomic DNA of the patient, instead alters the DNA of the patient's commensal bacteria, a far more tractable system. Probiotic intestinal bacteria such as members of the Lactobacillus family are routinely added to foods such as diary products, have essentially no pathology, and can be readily transformed with exogenous DNA. Lactobacillus transformed with therapeutic proteins and peptides or sets of enzymes to synthesize specific drugs may therefore represent a versatile platform for sustainable therapy. We will determine the optimal strains of Lactobacillus for expression in mice as a model organism and perform additional engineering of the strain as necessary to ensure persistence in the intestinal tract and regulated expression of peptide or proteins. We will also develop methods for rapidly depleting the transformed bacteria without damaging other commensal bacteria, as a safety precaution against the advent of any unexpected adverse responses during the use of these therapeutically transformed bacteria. We will then examine the effect on atherosclerosis-prone mice of expressing peptides with known therapeutic actions. Our final aim will be to test the feasibility of producing small molecule drugs such as lovastatin in vivo by transforming the bacteria with the required synthetic enzymes.

慢性病患者数量持续增加需要长期使用治疗药物治疗的病症，例如高胆固醇血症、高血压、糖尿病和肥胖已被证明对对个人和医疗保健系统造成经济负担。传统的药物生产的方法是化学合成所需的化合物，然后纯化、配制和分配。我们建议调查一部小说长期药物生产和输送的方法：使用肠道益生菌转化以表达所需药物并接种到慢性病患者体内定植和治疗生产。这种方法本质上采用了以下概念基因疗法不是改变患者的基因组DNA，而是改变患者共生细菌的 DNA，这是一个更容易处理的系统。益生菌肠道细菌，例如乳酸菌家族的成员，通常被添加到食品，例如乳制品，基本上没有病理学，并且可以很容易地用外源DNA转化。用治疗性蛋白质转化的乳杆菌因此，合成特定药物的肽或酶组可能代表可持续治疗的多功能平台。我们将确定最佳菌株乳酸杆菌作为模型生物在小鼠中表达并执行额外的操作根据需要对菌株进行改造，以确保其在肠道中的持久性肽或蛋白质的调节表达。我们还将开发快速的方法在不损害其他共生细菌的情况下耗尽转化的细菌，作为安全预防措施，防止在治疗期间出现任何意外的不良反应使用这些经过治疗的转化细菌。然后我们将检查其影响表达具有已知治疗作用的肽的易患动脉粥样硬化的小鼠。我们的最终目标是测试生产小分子药物的可行性，例如通过用所需的合成酶转化细菌来在体内产生洛伐他汀。