Micro-RNAs: a new mechanism negatively regulating B cell responses in the elderly

Micro-RNA：负向调节老年人 B 细胞反应的新机制

• 批准号: 8635965
• 负责人: BONNIE B. BLOMBERG
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635965
• 关键词: 3' Untranslated Regions; Age; Aging; Antibodies; Antibody Formation; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Binding Sites; Biological Markers; Cardiac; Cell Aging; Cell Culture Techniques; Cell physiology; Cells; Communicable Diseases; Data; Defect; Development; Disease; Elderly; Electrophoretic Mobility Shift Assay; Future; Gene Targeting; Goals; Grant; Health; Human; Immune response; Immune system; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Impairment; In Vitro; Individual; Infectious Agent; Inflammation; Inflammatory; Intervention; Lead; Malignant Neoplasms; Measures; MicroRNAs; Molecular; Mus; Nervous system structure; Oligonucleotides; Pathway interactions; Process; Proteins; Protocols documentation; Quality of life; RNA; RNA Stability; Refractory; Sorting - Cell Movement; System; TIS11 protein; TNF gene; Testing; Therapeutic; Time; Transcript; Up-Regulation; Vaccine Antigen; Vaccines; activation-induced cytidine deaminase; age related; aged; analog; cell age; cell type; design; follow-up; helix-loop-helix protein E47; impaired capacity; improved; in vivo; influenza virus vaccine; innovation; mRNA Stability; promoter; public health relevance; research study; response; transcription factor; young adult

DESCRIPTION (provided by applicant): Aging generates a decline in the ability of the individual to mount protective immune responses. The aged immune system also negatively impacts other important systems, such as the cardiac and nervous systems, by contributing to increased inflammation. The aged immune system not only impacts the quality of life of the individual but also the ability to be protected from infectious agents and cancers. We have shown that aging is associated with autonomous defects in B cells which are important for optimal health because they produce antibodies necessary for responses to vaccines and infectious diseases as well as other functions. These defects/biomarkers include: immunoglobulin (Ig) class switch recombination (CSR), activation-induced cytidine deaminase (AID) and the transcription factor E47. AID is necessary for CSR, the process that generates protective antibodies, and is a good measure of B cell function. We hypothesize that a mechanism for the aged impairment in B cell function, for which we have preliminary data, is that microRNA (miR)-155, miR-16 and other miRs are significantly higher in aged as compared with young adult unstimulated human B cells, making them "refractory" to further stimulation with the result of lower levels of AID induced after B cell stimulation. The objectives of this proposal are to identify miRs up-regulated in unstimulated B cells from elderly individuals, characterize the molecular pathways for their up-regulation as well as their mechanism of action, and begin to correct these defects by designing oligonucleotides which target these miRs. We propose to sort subsets of B cells, perform a miR microarray and correlate levels of the most increased miRs with AID. In the second aim we will identify molecular mechanisms for increases of particular miRs in aged B cells as well as for particular miRs down-regulating AID. In the third aim we will evaluate if lower in vitro CSR can be "rescued" by adding oligonucleotides blocking particular miR function (antagomirs) to B cell cultures. The experiments proposed in this grant offer an innovative approach to further characterize mechanisms which decrease B cell responses in elderly individuals. These studies should contribute to development of effective therapeutic strategies to protect elderly individuals from diseases typical of old age.

描述（由申请人提供）：衰老会导致个体发起保护性免疫反应的能力下降。老化的免疫系统还会导致炎症增加，从而对心脏和神经系统等其他重要系统产生负面影响。老化的免疫系统不仅影响个人的生活质量，而且影响免受传染源和癌症的能力。我们已经证明，衰老与 B 细胞的自主缺陷有关，B 细胞对于最佳健康非常重要，因为它们产生对疫苗和传染病以及其他功能做出反应所必需的抗体。这些缺陷/生物标志物包括：免疫球蛋白 (Ig) 类转换重组 (CSR)、激活诱导的胞苷脱氨酶 (AID) 和转录因子 E47。 AID 对于 CSR（生成保护性抗体的过程）是必要的，并且是 B 细胞功能的良好衡量标准。我们推测，老年 B 细胞功能受损的机制是，与年轻成人未刺激的人类 B 细胞相比，老年人中的 microRNA (miR)-155、miR-16 和其他 miR 明显更高，对此我们已有初步数据。 ，使得它们对进一步的刺激“难以抵抗”，导致 B 细胞刺激后诱导的 AID 水平较低。该提案的目的是鉴定老年人未刺激的 B 细胞中上调的 miR，表征其上调的分子途径及其作用机制，并开始通过设计针对这些 miR 的寡核苷酸来纠正这些缺陷。我们建议对 B 细胞亚群进行分类，进行 miR 微阵列，并将增加最多的 miR 水平与 AID 相关联。在第二个目标中，我们将确定衰老 B 细胞中特定 miR 增加以及特定 miR 下调 AID 的分子机制。在第三个目标中，我们将评估是否可以通过向 B 细胞培养物中添加阻断特定 miR 功能（antagomirs）的寡核苷酸来“挽救”较低的体外 CSR。这项资助中提出的实验提供了一种创新方法，可以进一步表征减少老年人 B 细胞反应的机制。这些研究应有助于制定有效的治疗策略，以保护老年人免受老年典型疾病的影响。

项目成果

Aging of the immune system: Focus on inflammation and vaccination.

• DOI: 10.1002/eji.201546178
• 发表时间: 2016-10
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Pinti, Marcello;Appay, Victor;Campisi, Judith;Frasca, Daniela;Fulop, Tamas;Sauce, Delphine;Larbi, Anis;Weinberger, Birgit;Cossarizza, Andrea
• 通讯作者: Cossarizza, Andrea

Immunophenotyping of Human B Lymphocytes in Blood and in Adipose Tissue.

血液和脂肪组织中人 B 淋巴细胞的免疫表型分析。

• DOI: 10.1007/978-1-4939-9650-6_7
• 发表时间: 2019
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Diaz,Alain;Romero,Maria;Frasca,Daniela;Blomberg,BonnieB
• 通讯作者: Blomberg,BonnieB