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Molecular characterization of the role for metabolites in immune cell differentiation

代谢物在免疫细胞分化中作用的分子表征

基本信息

批准号：
10455211
负责人：
Amy Susan Weinmann
金额：
$ 32.07万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-04 至 2022-09-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455211
关键词：
Acetates Acetyltransferase Address Antimetabolites Area Butyrates CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Differentiation process Cells Cellular Structures Communicable Diseases Complex DNA DNA Methylation Data Deacetylase Development Diet Dietary Intervention Differentiated Gene Disease Elements Enhancers Epigenetic Process Equilibrium Event Funding Gene Expression Profile Genes Genetic Variation Genome Genomics Grant Histone Acetylation Histones Human Human Genome Immune Immune System Diseases Immune response Immunology Individual Interleukin-2 Intervention Investigation Malignant Neoplasms Memory Metabolic Metabolism Modification Molecular Mus Nutrient Oncogenes Pathogenicity Patients Play Population Process Publishing Regulation Role Site Specificity T cell differentiation T-Lymphocyte Testing Therapeutic Time Variant Volatile Fatty Acids alpha ketoglutarate base cancer cell cell type chemotherapy dietary histone methylation immunopathology microbiome mouse genome programs promoter recruit response side effect transcription factor

项目摘要

Abstract The dynamic regulation of metabolic states plays an active role in cellular differentiation decisions, and this occurs throughout mammalian development. The conservation of these processes in different species, developmental settings, and immune cell types suggests metabolism influences common mechanistic events needed for differentiation decisions in diverse cellular backgrounds. However, the interpretation of these conserved mechanisms must have a component of cell-type specificity to properly regulate the genome to promote appropriate differentiation in individual cellular settings. Therefore, it is important to define the conserved and cell-type specific mechanistic principles to understand how dietary and metabolic interventions influence immune cell differentiation in the context of healthy and disease states. In the previous funding cycle of this grant, we identified a role for alpha-ketoglutarate (αKG) in regulating the IL-2-sensitive gene program in T cells. Mechanistically, αKG-sensitive events enhanced the association of CTCF with a subset of sites in CD4+ T cells, and together with studies in cancer cells, the data indicated this overall activity is conserved in diverse cell-types. The data also suggested these events are interpreted in a cell-type specific manner, potentially based on the enhancer landscape of the cell. In this grant, we will extend these findings to address how αKG-sensitive CTCF sites are selected, and whether there are any cell-type dependent mechanisms selecting these sites. We will also define whether downstream mechanisms, such as enhancer activity, have sensitivity to metabolic states. In this context, we will address whether the enhancer landscape is regulated by short chain fatty acids such as butyrate and acetate. We will also define which aspects of metabolite-sensitive mechanisms are conserved between species, and how variation between the mouse and human genome influences the interpretation of conserved and cell-type specific events. Information gained in these studies will be critical for predicting the role for metabolic and dietary interventions in the treatment of immunological diseases or in promoting effective immune responses to infectious diseases.

抽象的代谢状态的动态调节在细胞分化决策中发挥着积极作用，这发生在哺乳动物的整个发育过程中。这些过程在不同物种中的保存，发育环境和免疫细胞类型表明新陈代谢影响常见的机制事件不同细胞背景下的分化决策所需。然而，这些解释保守机制必须具有细胞类型特异性的组成部分，以正确调节基因组促进个体细胞环境的适当分化。因此，定义保守和细胞类型特定的机制原理，以了解饮食和代谢干预如何在健康和疾病状态下影响免疫细胞分化。在上一个融资周期中利用这笔资金，我们确定了 α-酮戊二酸 (αKG) 在调节 IL-2 敏感基因程序中的作用 T细胞。从机制上讲，αKG 敏感事件增强了 CTCF 与 CD4+ T 细胞，以及对癌细胞的研究，数据表明这种总体活性在不同的细胞类型。数据还表明这些事件以细胞类型特定的方式进行解释，可能基于细胞的增强子景观。在这笔赠款中，我们将扩展这些发现来解决如何选择αKG敏感的CTCF位点，以及是否存在任何细胞类型依赖性机制选择这些网站。我们还将定义下游机制（例如增强子活性）是否具有对代谢状态的敏感性。在这种情况下，我们将讨论增强子景观是否受以下因素调节：短链脂肪酸，例如丁酸和乙酸。我们还将定义代谢物敏感的哪些方面机制在物种之间是保守的，以及小鼠和人类基因组之间的变异如何影响保守事件和细胞类型特定事件的解释。在这些研究中获得的信息将对于预测代谢和饮食干预在免疫学治疗中的作用至关重要疾病或促进对传染病的有效免疫反应。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metabolites, genome organization, and cellular differentiation gene programs.

DOI：
10.1016/j.coi.2018.01.005
发表时间：
2018-04
期刊：
Current opinion in immunology
影响因子：
7
作者：
Chisolm DA;Weinmann AS
通讯作者：
Weinmann AS

Multiple mutant T alleles cause haploinsufficiency of Brachyury and short tails in Manx cats.

DOI：
10.1007/s00335-013-9471-1
发表时间：
2013-10
期刊：
MAMMALIAN GENOME
影响因子：
2.5
作者：
Buckingham, Kati J.;McMillin, Margaret J.;Brassil, Margaret M.;Shively, Kathryn M.;Magnaye, Kevin M.;Cortes, Alejandro;Weinmann, Amy S.;Lyons, Leslie A.;Bamshad, Michael J.
通讯作者：
Bamshad, Michael J.

T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow.

NK 细胞中 T-bet 依赖性 S1P5 表达促进淋巴结和骨髓的流出。

DOI：
10.1084/jem.20090525
发表时间：
2009-10-26
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Jenne CN;Enders A;Rivera R;Watson SR;Bankovich AJ;Pereira JP;Xu Y;Roots CM;Beilke JN;Banerjee A;Reiner SL;Miller SA;Weinmann AS;Goodnow CC;Lanier LL;Cyster JG;Chun J
通讯作者：
Chun J

Topologically associating domains are disrupted by evolutionary genome rearrangements forming species-specific enhancer connections in mice and humans.

DOI：
10.1016/j.celrep.2022.110769
发表时间：
2022-05-03
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Gilbertson, Sarah E.;Walter, Hannah C.;Gardner, Katherine;Wren, Spencer N.;Vahedi, Golnaz;Weinmann, Amy S.
通讯作者：
Weinmann, Amy S.

Transcriptional regulation of T cell metabolism.

T细胞代谢的转录调节。