N-3 PUFAs and antigen presenting cells

N-3 PUFA 和抗原呈递细胞

• 批准号: 7934812
• 负责人: SAAME R SHAIKH
• 金额: $ 42.61万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934812
• 关键词: Address; Animals; Antigen Presentation Pathway; Antigen-Presenting Cells; Applications Grants; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Biological; Biological Assay; CD8B1 gene; Calcium; Cell Culture Techniques; Cell membrane; Cell physiology; Cell surface; Cells; Cholesterol; Clinic; Confocal Microscopy; Data; Dendritic Cells; Development; Diet; Disease; Docosahexaenoic Acids; Eicosapentaenoic Acid; Excision; Fatty Acids; Flow Cytometry; Fluorescence Polarization; Fluorescence Resonance Energy Transfer; Goals; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Image; Immune; Immunosuppression; Immunosuppressive Agents; In Vitro; Infectious Agent; Inflammation; Inflammatory; Laboratories; Lateral; Life; Lipids; Liposomes; Major Histocompatibility Complex; Measures; Membrane Microdomains; Membrane Proteins; Microscopy; Modeling; Molecular Target; Mus; N-3 polyunsaturated fatty acid; Pathway interactions; Peripheral; Phospholipids; Polarization Microscopy; Polyunsaturated Fatty Acids; Proteins; Role; Signaling Molecule; Sphingolipids; Supporting Cell; Surface Antigens; Synapses; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Transgenic Mice; Up-Regulation; cytokine; immunological synapse; in vitro Model; nanoscale; public health relevance; research study; response

DESCRIPTION (provided by applicant): N-3 polyunsaturated fatty acids (PUFAs) exert immunosuppressive effects and have great potential as nutraceuticals for the treatment of inflammation associated disorders. A major limitation of using these fatty acids in the clinic as immunosuppressants is a poor understanding of their targets and molecular mechanisms. In vitro studies from our laboratory show that n-3 PUFAs suppress the function of antigen presenting cells (APCs) through the major histocompatibility complex (MHC) class I antigen presentation pathway by modifying the biophysical organization of the APC plasma membrane. The goal of this proposal is to test our in vitro model at the whole animal level in order to establish biological relevance. Our central hypothesis is that n-3 PUFA acyl chains form organizationally distinct nanometer scale plasma membrane domains that disrupt the distribution of sphingolipid/cholesterol-rich lipid rafts and thereby disrupt the lateral organization of MHC class I molecules (Specific Aim 1). By altering MHC class I lateral organization, the APC does not form a stable immunological synapse, which suppresses the ability of the APC to efficiently activate a na¿ve CD8+ T cell (Specific Aim 2). We will also test our hypothesis with the MHC class II pathway to address whether the effects of n-3 PUFAs on APC plasma membrane organization and subsequent function are limited to one pathway of antigen presentation or if the effects can be generalized to another pathway (Specific Aim 2). To test our model, we will rely on a combination of biophysical microscopies and functional immunological assays. If our hypothesis is correct, we will establish that dietary n-3 PUFAs can disrupt lipid and protein membrane organization on a nanometer scale and thereby suppress APC function. Given that APCs have a role in the removal of autoantigens and infectious agents, the studies proposed here will assist in the development of n-3 PUFAs as nutraceuticals for the treatment of inflammatory and autoimmune disorders, while minimizing their potential drawbacks. PUBLIC HEALTH RELEVANCE: N-3 polyunsaturated fatty acids (PUFAs) have potential therapeutic value for the treatment of inflammation associated disorders; however, their targets and mechanisms are poorly understood. This grant proposal aims to test a new model on how n-3 PUFAs modify the function of specific immune cells. Data generated from this proposal will contribute to the development n-3 PUFAs as nutraceuticals.

描述（由申请人提供）：N-3多不饱和脂肪酸（PUFAs）具有免疫抑制作用，作为治疗炎症相关疾病的营养保健品具有巨大潜力。在临床上使用这些脂肪酸作为免疫抑制剂的一个主要限制是对其靶点和分子机制的了解不足。我们实验室的体外研究表明，n-3 PUFAs通过改变APC质膜的生物物理组织，通过主要组织相容性复合体（MHC） I类抗原呈递途径抑制抗原呈递细胞（APC）的功能。本提案的目标是在整个动物水平上测试我们的体外模型，以建立生物学相关性。我们的中心假设是n-3 PUFA酰基链形成组织上不同的纳米级质膜结构域，破坏鞘脂/富含胆固醇的脂筏的分布，从而破坏MHC I类分子的横向组织（Specific Aim 1）。通过改变MHC I类横向组织，APC不能形成稳定的免疫突触，这抑制了APC有效激活na - ve CD8+ T细胞的能力（Specific Aim 2）。我们还将用MHC II类途径验证我们的假设，以确定n-3 PUFAs对APC质膜组织和随后功能的影响是否仅限于抗原呈递的一种途径，或者是否可以推广到另一种途径（Specific Aim 2）。为了测试我们的模型，我们将依靠生物物理显微镜和功能免疫学分析的结合。如果我们的假设是正确的，我们将确定膳食n-3 PUFAs可以在纳米尺度上破坏脂质和蛋白质膜组织，从而抑制APC功能。鉴于apc在去除自身抗原和感染因子方面发挥作用，本文提出的研究将有助于开发n-3 PUFAs作为治疗炎症和自身免疫性疾病的营养保健品，同时最大限度地减少其潜在的缺点。