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）细胞在对病毒感染的免疫反应以及消除压力或转化细胞的免疫反应中起重要作用。它们还可以通过产生炎症细胞因子和树突状细胞功能的调节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疗法的有吸引力的候选者。但是，我们对控制NK细胞发育和功能的机制的理解不足，无法预测NK细胞反应的治疗操作结果。我的研究集中在理解控制先天和适应性淋巴细胞发育的分子机制上，重点是E蛋白螺旋螺旋 - 环螺旋转录因子及其ID蛋白的拮抗剂。 ID2对于NK细胞开发至关重要，但是它的功能以及是否需要适当的NK细胞成熟和功能所必需的它仍然难以捉摸，我们将检验以下假设：ID2对于成熟（M）NK细胞的终末成熟是必需的，因此会影响NK细胞对病毒感染的反应，从而限制了NK细胞中的免疫记忆。我们假设ID2的功能充分限制了E蛋白活性，以限制其向交替的淋巴细胞命运分化的潜力，但允许E蛋白激活在MNK细胞子集中需要的T细胞相关信号蛋白的子集。我们将确定由ID2抑制的E蛋白来改变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的功能置于控制NK细胞发育和功能的转录调节剂的LARGR网络中，并将有助于我们理解治疗干预措施将如何影响NK细胞反应。