Molecular signature of inflammation

炎症的分子特征

基本信息

批准号：
9005843
负责人：
Subramaniam Malarkannan
金额：
$ 32.26万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-10 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9005843
关键词：
Acute Address Affect Antibodies Asthma Autoimmune Diseases B-Cell Lymphomas Binding Binding Sites CD19 gene CD8B1 gene Cancer Patient Cause of Death Cell-Mediated Cytolysis Cells Chronic Collection Cytoplasmic Granules DNA Sequence Data Disease Fever Goals Granulocyte-Macrophage Colony-Stimulating Factor Health Hematologic Neoplasms Histamine Human Hypersensitivity Hypotension Immune response Immunology Immunotherapeutic agent Immunotherapy In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interferon Type II Intervention Lymphocyte Lymphoma MAP3K7 gene MAPK3 gene MAPK8 gene Mediating Mediator of activation protein Methods Modeling Molecular Molecular Profiling Molecular Target Mus NF-kappa B Natural Immunity Natural Killer Cells Nature Outcome Pathway interactions Peptides Phase I Clinical Trials Play Population Production Prostaglandins Pulmonary Edema RANTES Role Signal Transduction Signaling Molecule Signaling Protein Syndrome T-Lymphocyte Testing Therapeutic Transcription Factor AP-1 Validation Work base cancer risk chemokine chimeric antigen receptor clinically relevant cytokine cytotoxicity in vivo innovation killings neoplastic cell novel pre-clinical preclinical efficacy tumor

项目摘要

DESCRIPTION (provided by applicant): Inflammation is a critical component of an immune response. However, acute or chronic inflammation is highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma, multiple autoimmune disorders and increased risk of cancer. Inflammation is also a major limiting factor in the successful utilization of genetically-modified NK or T cell-based immunotherapy. Thus, inflammation is a major health concern with high clinical relevance. Inflammation is caused by soluble mediators, including prostaglandins, histamine, lysosomal granules and cytokines or chemokines (IFN-γ, GM-CSF, MIP-1α, MIP-ß and RANTES). NK cells that are the major lymphocyte population of the innate immunity, produce many of these factors and thereby play a central role in causing pathological conditions. Exclusive intracellular signaling molecules that are responsible for the production of inflammatory mediators in lymphocytes are largely unknown. Using NK cells, we have recently identified unique molecules that are exclusively responsible for the production of inflammatory cytokines or chemokines. Our findings identify signaling protein ADAP as a novel molecular target to successfully treat many inflammatory disorders. This will be achieved by exclusively blocking the production of inflammatory cytokines/chemokines without impairing other effector functions, including cytotoxicity. Using these findings, we propose to formulate an effective NK cell-mediated immunotherapy for cancer patients with augmented anti-tumor cytotoxicity without the associated inflammation ('cytokine-release syndrome'). Our long term goals are to formulate innovative therapeutic approaches to reduce inflammation in a variety of diseases. Here, we propose the following. Aim-1: Evaluate tumor killing and inflammatory cytokine production in vivo, using ADAP-/- mice. Aim-2: Formulate a molecular intervention to contain inflammatory cytokines from NK cells. Aim-3: Determine the preclinical efficacy of ADAP-derived minimal 'decoy' peptide.

描述（应用程序提供）：炎症是免疫响应的关键组成部分。但是，急性或慢性感染具有高度破坏性。不受控制的注射构成了过敏，哮喘，多种自身免疫性疾病和癌症风险增加的基础。炎症也是成功利用一般修饰的NK或基于T细胞的免疫疗法的主要限制因素。这是高临床相关性的主要健康问题。炎症是由固体介质引起的，包括前列腺素，组胺，溶酶体颗粒和细胞因子或趋化因子（IFN-γ，GM-CSF，MIP-1α，MIP-ß和Rantes）。是先天免疫学的主要淋巴细胞种群的NK细胞产生许多因素，从而在引起病理状况中起着核心作用。负责淋巴细胞中炎症介质产生的独家细胞内信号分子是未知的。使用NK细胞，我们最近确定了独特的分子，这些分子仅负责炎性细胞因子或趋化因子的产生。我们的发现确定信号蛋白ADAP是成功治疗许多炎症性疾病的新型分子靶标。这将通过仅阻止炎症细胞因子/趋化因子的产生而不损害其他效应子功能（包括细胞毒性）来实现。使用这些发现，我们建议为具有增强的抗肿瘤细胞毒性的癌症患者制定有效的NK细胞介导的免疫疗法，而无需相关感染（“细胞因子释放综合征”）。我们的长期目标是制定创新的治疗方法，以减少各种疾病的感染。在这里，我们提出以下内容。 AIM-1：使用ADAP - / - 小鼠在体内评估肿瘤杀伤和炎症性细胞因子的产生。 AIM-2：制定分子干预以含有来自NK细胞的炎性细胞因子。 AIM-3：确定ADAP衍生的最小“诱饵”肽的临床前效率。