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（由应用提供）：N-3多不饱和脂肪酸（PUFAS）执行免疫抑制作用，并且具有很大的潜力，可以作为治疗感染相关疾病的营养素。在临床中使用这些脂肪酸作为免疫抑制剂的主要局限性是对其靶标和分子机制的不良理解。我们实验室的体外研究表明，N-3 PUFA通过主要的组织相容性复合物（MHC）I类抗原表现途径抑制抗原呈递细胞（APC）的功能，通过修改APC质量质膜的生物物理组织。该建议的目的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酰基链形成了组织不同的纳米尺度质膜膜结构域，破坏了鞘脂/胆固醇富含脂质的脂质筏的分布，从而破坏了MHC I类分子的横向组织（特定目标1）。通过改变MHC I类横向组织，APC不会形成稳定的免疫突触，这抑制了APC有效激活NA¿VECD8+ T细胞的能力（特定目标2）。我们还将使用MHC II类途径测试我们的假设，以解决N-3 PUFAS对APC质膜组织的影响和随后的功能仅限于一种抗原呈递途径，还是可以将其推广到另一种途径（特定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测定的组合。如果我们的假设是正确的，我们将确定饮食中的N-3 PUFA可以以纳米量表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剂中发挥作用，因此此处提出的研究将有助于开发N-3 PUFAS作为营养物，以治疗炎症和自身免疫性疾病，同时最大程度地减少其潜在缺陷。 公共卫生相关性：N-3多不饱和脂肪酸（PUFAS）具有治疗相关疾病的治疗的潜在治疗价值；但是，他们的目标和机制知之甚少。该赠款提案旨在测试N-3 PUFA如何修改特定免疫细胞功能的新模型。该提案产生的数据将有助于作为营养剂的开发N-3 PUFA。