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）：衰老会导致个体产生保护性免疫反应的能力下降。衰老的免疫系统还会对心脏和神经系统等其他重要系统产生负面影响，导致炎症增加。衰老的免疫系统不仅会影响个体的生活质量，还会影响其免受传染病和癌症侵害的能力。我们已经证明，衰老与B细胞的自主缺陷有关，B细胞的自主缺陷对最佳健康非常重要，因为它们产生对疫苗和传染病以及其他功能作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）类开关重组（CSR）、激活诱导胞苷脱氨酶（AID）和转录因子E47。AID对于CSR（产生保护性抗体的过程）是必需的，并且是衡量B细胞功能的良好指标。我们假设老年B细胞功能受损的机制，我们有初步的数据，是microRNA (miR)-155， miR-16和其他miRs在老年人中明显高于年轻成人未刺激的人B细胞，使其“难以”进一步刺激，B细胞刺激后诱导的AID水平较低。本研究的目的是鉴定老年人未受刺激的B细胞中上调的miRs，表征其上调的分子途径及其作用机制，并开始通过设计靶向这些miRs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，执行miR微阵列，并将最多增加的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miRs增加的分子机制以及特定miRs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功能的寡核苷酸（拮抗剂）来“拯救”体外较低的CSR。在这项资助中提出的实验提供了一种创新的方法来进一步表征老年人减少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侵害。

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