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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：衰老会导致个人安装保护性免疫反应的能力下降。老年免疫系统还通过增加炎症来对其他重要系统（例如心脏和神经系统）产生负面影响。老年免疫系统不仅会影响个人的生活质量，而且还影响了免受感染剂和癌症的保护能力。我们已经表明，衰老与B细胞中的自主缺陷有关，这对于最佳健康很重要，因为它们产生了对疫苗和传染病以及其他功能的反应所必需的抗体。这些缺陷/生物标志物包括：免疫球蛋白（IG）类开关重组（CSR），激活诱导的胞苷脱氨酶（AID）和转录因子E47。辅助是CSR所必需的，CSR是生成保护性抗体的过程，并且是B细胞功能的良好量度。我们假设，您具有初步数据的B细胞功能中老化损伤的机制是，与年轻的成人未刺激的人类B细胞相比，MicroRNA（miR）-155，miR-16和其他miR在老年人中显着更高，使其“折射”以较低的辅助剂量刺激了B细胞刺激后，使其“使其”进一步刺激。该提案的目标是识别来自老年人的未刺激的B细胞中上调的miR，表征其上调的分子途径及其作用机理，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细胞的子集进行排序，执行miR微阵列，并将MIR的最大水平与AID相关。在第二个目标中，我们将确定年龄B细胞中特定MIR的增加以及特定的MIR下调辅助的分子机制。在第三个目的中，我们将通过在B细胞培养物中添加寡核苷酸（Antagomirs）来评估是否可以“营救”较低的体外CSR。该赠款中提出的实验提供了一种创新的方法，可以进一步表征机制，从而降低了老年人的B细胞反应。这些研究应有助于制定有效的治疗策略，以保护老年人免受典型的老年疾病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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。