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：
8791299
负责人：
BARBARA L. KEE
金额：
$ 48.39万
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/8791299
关键词：
Affect Alleles Applications Grants B-Lymphocytes Biological Assay Bone Marrow Cell Lineage Cell Maturation Cell Survival Cell physiology Cells Data Dendritic Cells Development E protein Effector Cell Event Failure Gene Deletion Gene Expression Genes Genetic Transcription Goals Granzyme Health 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 neoplasm immunotherapy novel prevent progenitor protein E protein expression protein function recombinase research study response transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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 developmet 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 alterntive 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 largr 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.

描述（由申请人提供）：自然杀伤（NK）细胞在病毒感染的免疫反应以及消除应激或转化细胞中发挥着重要作用。它们还可以通过产生炎症细胞因子和调节树突状细胞功能来影响适应性免疫反应。它们杀死转化细胞并影响适应性免疫的能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不足以让我们预测 NK 细胞反应的治疗操作的结果。我的研究重点是了解控制先天性和适应性淋巴细胞发育的分子机制，重点是 E 蛋白螺旋-环-螺旋转录因子及其 Id 蛋白的拮抗剂。 Id2 对于 NK 细胞的发育至关重要，但它如何发挥作用以及它是否是 NK 细胞正常成熟和功能所必需的仍然是个谜。 NK 细胞对病毒感染的反应，从而限制了 NK 细胞群的免疫记忆。我们假设 Id2 的作用是充分限制 E 蛋白的活性，以限制其分化为不同淋巴细胞命运的潜力，同时允许 E 蛋白激活 mNK 细胞亚群所需的 T 细胞相关信号蛋白亚群。我们将确定被 Id2 抑制的 E 蛋白改变 NK 谱系细胞的命运和功能的分子机制。我们的研究将使我们能够将 E 蛋白和 Id2 的功能放入控制 NK 细胞发育和功能的大型转录调节因子网络中，并将有助于我们了解治疗干预措施如何影响 NK 细胞反应。