Regulation of Lymphocyte Development by HLH Proteins

HLH 蛋白对淋巴细胞发育的调节

基本信息

批准号：
8638491
负责人：
BARBARA L. KEE
金额：
$ 38.39万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-15 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638491
关键词：
Affect Alleles Applications Grants B-Lymphocytes Biological Assay Bone Marrow Cell Lineage Cell Maturation Cell Survival Cell physiology Cells Commit Data Dendritic Cells Development E protein Effector Cell Event Failure Gene Deletion Gene Expression Genes Genetic Transcription Goals Granzyme Helix-Turn-Helix Motifs ITGAM gene Immune Immune response Immune system Immunologic Memory Immunotherapy In Vitro Inflammatory Intervention Lymphocyte Lymphoid Maintenance Malignant - descriptor Malignant Neoplasms Memory Modeling Molecular Multipotent Stem Cells Mus Natural Killer Cells Outcome Play Population Process Production Proteins Regulation Research Role Signal Pathway Signaling Protein Specific qualifier value Stress T cell differentiation T-Cell Development T-Lymphocyte Subsets TCF3 gene Tamoxifen Testing Therapeutic Therapeutic Intervention Transplantation Virus Virus Diseases adaptive immunity base cancer cell cancer immunotherapy cell transformation cytokine gene function helix-loop-helix protein differentiation inhibitor in vivo inhibitor/antagonist insight killings leukemogenesis mRNA Expression novel prevent progenitor protein E protein expression protein function public health relevance recombinase research study response transcription factor tumor

项目摘要

Project Summary Natural killer (NK) cells play an important role in the immune response to viral infection and in the eradication of stressed or transformed cells. They can also influence adaptive immune responses through production of inflammatory cytokines and modulation of dendritic cell function. Their ability to kill transformed cells and influence adaptive immunity has made them an attractive candidate for tumor immunotherapy. However, our understanding of the mechanisms controlling NK cell development and function are inadequate to allow us to predict the outcome of therapeutic manipulations on NK cell response. My research is focused on understanding the molecular mechanisms controlling innate and adaptive lymphocyte development with an emphasis on the E protein helix-loop-helix transcription factors and their antagonists that Id proteins. Id2 is critical for NK cell development but how it functions and whether it is required for proper NK cell maturation and function has remained elusive We will test the hypothesis that Id2 is required for the terminal maturation of mature (m)NK cells and therefore influences the response of NK cells to virus infection thus limiting immunologic memory in the NK cell population. We hypothesize that Id2 functions to limit E protein activity sufficiently to restrain their potential for differentiation toward alternative lymphocyte fates yet allows E proteins to activate a subset of T cell-associated signaling proteins that are required in a subset of mNK cells. We will determine the molecular mechanism by which the E proteins, which are inhibited by Id2, function to alter the fate and function of NK lineage cells. Our studies will allow us to place the functions of E proteins and Id2 into the larger network of transcriptional regulators that control NK cell development and function and will contribute to our understanding of how therapeutic interventions will influence NK cell responses.

项目概要自然杀伤 (NK) 细胞在病毒感染的免疫反应中发挥重要作用以及消除应激或转化的细胞。它们还可以影响适应性通过产生炎症细胞因子和调节免疫反应树突状细胞功能。它们杀死转化细胞并影响适应性的能力免疫力使它们成为肿瘤免疫治疗的有吸引力的候选者。然而，我们对控制 NK 细胞发育和功能的机制的理解是不足以让我们预测 NK 细胞治疗操作的结果回复。我的研究重点是了解分子机制控制先天性和适应性淋巴细胞的发育，重点是 E 蛋白质螺旋-环-螺旋转录因子及其拮抗剂，即Id蛋白质。 id2 是对于 NK 细胞的发育至关重要，但它如何发挥作用以及是否需要它才能正常发育 NK 细胞的成熟和功能仍然难以捉摸我们将检验以下假设： Id2 是成熟 (m)NK 细胞终末成熟所必需的，因此会影响 NK 细胞对病毒感染的反应，从而限制 NK 中的免疫记忆细胞群。我们假设 Id2 的功能足以限制 E 蛋白的活性限制其分化为其他淋巴细胞命运的潜力，但允许 E 激活 T 细胞相关信号蛋白子集的蛋白质，这些蛋白是 mNK 细胞的子集。我们将确定E的分子机制被 Id2 抑制的蛋白质可改变 NK 谱系的命运和功能细胞。我们的研究将使我们能够将 E 蛋白和 Id2 的功能放入更大的控制 NK 细胞发育和功能的转录调节因子网络将有助于我们了解治疗干预措施如何影响 NK 细胞反应。