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Regulation of Atopic Immune Responses by the Prolyl lsomerase Cyclophillin A

脯氨酰异构酶亲环蛋白 A 对特应性免疫反应的调节

基本信息

批准号：
7763784
负责人：
JOHN D COLGAN
金额：
$ 34.77万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-15 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7763784
关键词：
Address Affect Allergic Disease Allergic Reaction Allergic inflammation Amino Acids Antigens Asthma Binding Biochemical Biological Assay Biological Process CD4 Positive T Lymphocytes Cell Culture System Cell physiology Cells Complex Cyclophilin A Cyclosporine Cyclosporins Cytoplasmic Protein Data Developed Countries Development Disease Event Extrinsic asthma Gene Delivery Genes Goals Grant Health Helper-Inducer T-Lymphocyte Hypersensitivity IgE Immune response Immunosuppressive Agents Inflammation Inflammatory Response Interleukin-4 LCP2 gene Ligands Ligation Modeling Molecular Mus Mutagenesis Mutation PLC gamma1 Pathway interactions Peptidylprolyl Isomerase Pharmaceutical Preparations Phospholipase Process Production Proline Protein Tyrosine Kinase Proteins Regulation Research Personnel Role Serum Severity of illness Signal Pathway Signal Transduction Signaling Molecule T cell differentiation T cell response T-Cell Receptor T-Lymphocyte Testing Th2 Cells Therapeutic Agents allergic response base cell type cytokine eosinophil mast cell mouse model mutant new therapeutic target overexpression peptide structure programs protein function protein protein interaction receptor response retroviral-mediated src Homology Region 2 Domain transcription factor

项目摘要

Asthma and other allergic diseases are widespread health problems for industrialized nations. In order to develop therapeutic agents that lessen the severity of these diseases, the biological processes that drive allergy need to be defined. Allergic reactions are triggered by excessive helper T cell responses to antigens; thus these cells are attractive targets for new therapeutics. The long-term objective of this proposal is to define specific intracellular signaling events within helper T cells that control the production of allergy- promoting cytokines such as IL-4. We have identified an important role for the cyclosporine receptor cyclophilin A (CypA) in regulating helper T cell responses. CypA alters the structure of peptide bonds adjacent to proline residues, and may thus regulate protein function by inducing conformational changes. Mice lacking CypA develop inflammation that contains eosinophils and mast cells, two cell types that have key roles in allergic responses. Helper T cells from these mice overproduce IL-4 and other allergy- associated cytokines and show increased activation of the key signaling molecule phospholipase C-gamma1 (PLCgl). A known regulator of PLCgl is Itk,a tyrosine kinase that controls IL-4 expression. CypA interacts with a proline residue in Itk ; this interaction promotes Itk self-association, which is postulated to downregulate Itk activity, and also inhibits contacts between Itk and other factors that promote PLCgl activation. Based on these findings, our central hypothesis is that CypA functions as represser of Itk activity, thus limiting IL-4 expression by helper T cells. To explore this hypothesis, we will pursue the following specific aims: 1) Identify amino acids that are required for interaction between Itk and CypA and for Itk self- association; biochemical assays will be used to assess how amino acid changes in Itk and CypA affect protein-protein interactions; 2) Determine the effects of mutations in CypA and Itk on function; CypA and Itk mutant proteins with altered function will be expressed in helper T cells to assess their impact onIL-4 expression and PLCgl activation; 3) Determine the role of CypA and Itk in allergic disease; how changes in CypA or Itk activity modulate asthma development in mouse model for this disease will be analyzed; 4) Determine whether CypA regulates the development of helper T cells that express allergy-promoting cytokines; a cell culture system will be used to define regulatory targets for CypA.

哮喘和其他过敏性疾病是工业化国家普遍存在的健康问题。为了…

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Signaling pathways critical for allergic airway inflammation.

DOI：
10.1097/aci.0b013e328334f642
发表时间：
2010-02
期刊：
Current opinion in allergy and clinical immunology
影响因子：
2.8
作者：
Colgan JD;Hankel IL
通讯作者：
Hankel IL

The Justy mutation identifies Gon4-like as a gene that is essential for B lymphopoiesis.

DOI：
10.1084/jem.20100147
发表时间：
2010-07-05
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Lu P;Hankel IL;Knisz J;Marquardt A;Chiang MY;Grosse J;Constien R;Meyer T;Schroeder A;Zeitlmann L;Al-Alem U;Friedman AD;Elliott EI;Meyerholz DK;Waldschmidt TJ;Rothman PB;Colgan JD
通讯作者：
Colgan JD