Toward a new approach to SLE therapy

寻找 SLE 治疗的新方法

基本信息

批准号：
8111099
负责人：
Betty Diamond
金额：
$ 35.86万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111099
关键词：
Ablation Affect African American Alpha Particles Anti-DNA Antibodies Antibiotics Antibodies Antigen-Antibody Complex Antigens Autoantibodies Autoimmune Diseases B-Cell Activation B-Lymphocytes Beta Particle Binding Brain Cerebrospinal Fluid Cessation of life Coupled DNA DNA Binding Dendritic Cells Dendritic cell activation Deposition Development Disease Disease Progression Genes Goals Half-Life Immune response Immunocompromised Host Immunosuppression In Vitro Incidence Infection Inflammatory Interferons Kidney L Forms Laboratories Latino Lupus Mediating Minority Mus N-Methyl-D-Aspartate Receptors Nephritis Neuraxis Neurons Nuclear Antigens Nucleic Acids Opportunistic Infections Oral Administration Organ Pathogenicity Pathology Patients Peptides Peripheral Blood Mononuclear Cell Plasma Probability Process Production Property Radioactive Radioisotopes Reagent Renal dialysis Research Serum Severities Specificity Systemic Lupus Erythematosus Therapeutic Tissues Toxic effect Translating Up-Regulation Woman assault autoreactivity base brain tissue design improved in vivo innovation insight mouse model neuropsychiatry novel strategies novel therapeutics outcome forecast public health relevance small molecule treatment strategy

项目摘要

DESCRIPTION (provided by applicant): This proposal focuses on the development of a new therapeutic for systemic lupus erythematosus. The overall goal is to 1) modify a peptide mimetope of DNA to increase serum half life, permit oral administration, and maximize function, 2) to explore the functionality of two new compounds with similar binding properties to the peptide and 3) develop additional compounds. The mimetope binds to a subset of anti-DNA antibodies that deposit in glomeruli, cross-react with NMDA receptors and mediate excitotoxic neuron death, and, in immune complexes, activate dendritic cells. Efforts will be made to use radioisotope-tagged peptide/modified compound to ablate antigen-specific B cells. It will also be determined if peptide intercalates into DNA-containing immune complexes to diminish activation of dendritic cells. Finally, new peptide mimetopes of DNA will be sought in case more than one subset of anti-DNA antibodies or DNA-reactive B cells must be eliminated to reduce disease pathology. PUBLIC HEALTH RELEVANCE: This proposal identifies a non-immunosuppressive strategy for the treatment of systemic lupus.

描述（由申请人提供）：该提案重点关注系统性红斑狼疮新疗法的开发。总体目标是 1) 修饰 DNA 的肽模拟表位以延长血清半衰期、允许口服给药并最大限度地发挥功能，2) 探索两种与肽具有相似结合特性的新化合物的功能，以及 3) 开发其他化合物。模拟表位与沉积在肾小球中的抗 DNA 抗体子集结合，与 NMDA 受体交叉反应并介导兴奋毒性神经元死亡，并在免疫复合物中激活树突状细胞。将努力使用放射性同位素标记的肽/修饰化合物来消除抗原特异性 B 细胞。还将确定肽是否插入含 DNA 的免疫复合物中以减少树突状细胞的活化。最后，如果必须消除多于一种的抗 DNA 抗体或 DNA 反应性 B 细胞以减少疾病病理，则将寻找新的 DNA 肽模拟表位。公众健康相关性：该提案确定了治疗系统性狼疮的非免疫抑制策略。