Targeting HSP70 in autoimmune vitiligo

靶向 HSP70 治疗自身免疫性白癜风

基本信息

批准号：
8928808
负责人：
I. Caroline Le Poole
金额：
$ 33.22万
依托单位：
LOYOLA UNIVERSITY CHICAGO
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：
2007-04-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8928808
关键词：
Address Affect Alopecia Areata Amino Acid Substitution Amino Acids Animals Antigen Mimicry Antigens Apoptosis Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Binding Biology C Type Lectin Receptors Cell physiology Cell surface Cells Charge Clinical Complement DNA Data Dendritic Cells Dendritic cell activation Development Disease Disease model Eukaryota Evolution Exhibits Family suidae Health Heat shock proteins Heat-Shock Proteins 70 Homologous Gene Human Immune response Infection Infiltration Inflammation Knock-out Knowledge Learning Life Link Maintenance Measures Mediating Modeling Modification Molecular Chaperones Mus Mutation NMR Spectroscopy Patients Peptides Peripheral Positioning Attribute Prevention Process Proteins Relative (related person)Role Safety Site Site-Directed Mutagenesis Skin Stress T-Cell Receptor T-Lymphocyte Testing Therapeutic Time To autoantigen Topical application Transgenic Mice Translating Vaccinated Vaccination Variant Vertebral column Vitiligo Work clinical application design efficacy testing extracellular gene gun immune activation melanocyte melanoma microbial model design mouse model mutant novel overexpression pre-clinical prevent prophylactic protein expression protein function protein misfolding receptor binding response safety testing stress protein theories uptake

项目摘要

DESCRIPTION (provided by applicant): We have generated a mutant version of inducible HSP70i with treatment potential for vitiligo. The resulting protein inhibits dendritic cell activaton and gene gun vaccinated mice exhibit markedly reduced depigmentation over time, associated with tolerized dendritic cell profiles and reduced T cell infiltration to the skin. Under the curret application, we want to learn about the underlying mechanism whereby mutant HSP70i affects immune activation. We propose that the remarkable changes observed in response to a single amino acid modification in human HSP70i relate to relative activation via CLRs versus TLRs. Differential APC activation may be conserved throughout evolution, as the microbial homolog of HSP70 elicits APC activation and inflammation, and conserved functions of the molecule may explain infection induced autoimmunity. Moreover, mutant HSP70i may impact the development of autoimmune disease beyond vitiligo. We propose to generate a manageable peptide of use for patient treatment, and to test the safety and efficacy of purified peptide treatment in a substrain of Sinclair swine with human-like skin and spontaneous vitiligo. These studies will greatly extend our knowledge of HSP70-induced vitiligo and provide preclinical data of use for translating our findings towards the treatment of human autoimmune disease.

描述（由申请人提供）：我们已经生成了具有诱导HSP70I的突变版本，具有白癜风的治疗潜力。所得的蛋白质抑制树突状细胞Activaton，而基因枪疫苗接种的小鼠随着时间的流逝显着降低了脱位，与耐受的树突状细胞谱相关，并减少了T细胞对皮肤的T细胞浸润。在库尔特应用下，我们想了解突变HSP70I会影响免疫激活的潜在机制。我们建议，在人类HSP70I中对单个氨基酸修饰的响应观察到的显着变化与通过CLR与TLR相对激活有关。由于HSP70的微生物同源物引起APC激活和炎症，并且该分子的保守功能可以解释感染诱导的自身免疫性，因此可以保留差异APC激活。此外，突变的HSP70I可能会影响白癜风以外的自身免疫性疾病的发展。我们建议生成可控制的肽用于患者治疗，并在辛克莱猪的基质中测试纯化的肽治疗的安全性和功效，并具有人类皮肤和自发性的绒毛。这些研究将大大扩展我们对HSP70诱导的白癜风的了解，并提供用于将我们的发现转化为治疗人自身免疫性疾病的临床前数据。