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Intracellular Signaling by the Precursor B Cell Receptor

前体 B 细胞受体的细胞内信号传导

基本信息

批准号：
7452363
负责人：
CHRISTOPHER AJ ROMAN
金额：
$ 7.65万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7452363
关键词：
Affect Agammaglobulinemia Antibodies Antigens B-Cell Development B-Lymphocytes Biological Biological Models Bone Marrow CD22 gene Cell Culture System Cell membrane Cell model Cell surface Cells Chronic Lymphocytic Leukemia Complex Cultured Cells Cytoplasmic Tail Data Development Endosomes Exclusion Flow Cytometry Golgi Apparatus Human Immune Immune response Interleukin-7 Ligands Link Localized Lymphoid Mature B-Lymphocyte Modeling Molecular Molecular Weight Mus Mutation Organ Pathology Peripheral Physiological Process Property Proteins Purpose Receptor Signaling Receptors, Antigen, B-Cell Research Project Grants Signal Transduction Site Surface Test Result Testing Transducers Transgenes Transgenic Mice Transgenic Organisms Tyrosine Phosphorylation abl Oncogene cell transformation extracellular in vivo leukemia/lymphoma loss of function mutation mu-Chain Immunoglobulins receptor research study

项目摘要

DESCRIPTION (provided by applicant): Signals transduced by the precursor B cell receptor (preBCR) are necessary for B cell development. Humans and mice genetically deficient in preBCR components suffer from an absence or paucity of pre-B and more mature B cells that is responsible for a state of agammaglobulinemia and resultant severe immune deficiency. Deregulating or loss-of-function mutations of downstream preBCR signal transduction molecules are associated with B cell leukemia and lymphoma. An enigmatic aspect of preBCR signaling is the physiological means by which receptor signaling is activated. Evidence for both ligand-dependent and ligand-independent mechanisms has been demonstrated in cell culture systems and suggested to be physiological. Common to both models has been the idea that receptor localization to the cell surface is critical, either to engage ligands or key signal transduction molecules that reside there, because surface expression has directly correlated with receptor activity. Contrary to this model, we have recently demonstrated that preBCR complexes directed away from the cell membrane and redistributed among intracellular, post-ER compartments were as or nearly as active as wild-type preBCRs. This was accomplished by appending endomembrane localization sequences to the cytoplasmic tail of a preBCR-forming immunoglobulin mu heavy chain (Ig HC), and testing the resulting "redirected" preBCR activity in preBCR-deficient transformed and primary pro-B cells. These data support the model that preBCRs do not require extracellular ligands at the cell surface for signaling, and that the preBCR is active in post-ER compartments like the Golgi. However, several developmentally important processes linked to preBCR signaling, such as allelic exclusion, could not be evaluated, and it remains possible that these require activities dependent on preBCR surface expression. Therefore, the purpose of the experiments in this small R03 proposal is to build on these findings by evaluating the biological activity of these redirected preBCR complexes in vivo. This will be accomplished in one Aim by establishing transgenic mice that express the redirected Ig HCs and evaluating their ability to support B cell development and effect allelic exclusion in genetically preBCR-deficient and preBCR-sufficient mice. This information will be important to better understand the molecular mechanisms that determine receptor activity in normal immune development and in B cell pathologies. The experiments in this proposal aim to understand how a critical molecule known as the preBCR controls the development of B cells, the cells that make antibodies essential for an immune response. People that are genetically unable to make a preBCR are severely immune deficient. The information obtained is needed to better understand the origin of some B cell leukemias that can be traced to mutations that affect the functioning of the preBCR.

描述（由申请人提供）：由前体B细胞受体（preBCR）转导的信号是B细胞发育所必需的。人类和小鼠在基因上缺乏前bcr成分，会导致前B细胞和更成熟的B细胞缺失或缺乏，从而导致双球蛋白血症和由此导致的严重免疫缺陷。下游前bcr信号转导分子的失调或功能缺失突变与B细胞白血病和淋巴瘤有关。preBCR信号传导的一个神秘方面是受体信号被激活的生理手段。在细胞培养系统中已经证明了配体依赖性和配体非依赖性机制的证据，并认为这是生理上的。这两种模型的共同点是，受体在细胞表面的定位是至关重要的，无论是参与配体还是驻留在那里的关键信号转导分子，因为表面表达与受体活性直接相关。与该模型相反，我们最近证明了preBCR复合物远离细胞膜并在细胞内、er后室中重新分布，与野生型preBCR一样或几乎一样活跃。这是通过将膜定位序列附加到形成pre - bcr的免疫球蛋白重链（Ig HC）的细胞质尾部来完成的，并在pre - bcr缺陷转化和原代前b细胞中测试由此产生的“重定向”的pre - bcr活性。这些数据支持了preBCR不需要细胞表面的细胞外配体来传递信号的模型，并且preBCR在er后区室（如高尔基体）中是活跃的。然而，一些与preBCR信号相关的重要发育过程（如等位基因排斥）无法评估，这些过程仍然可能需要依赖于preBCR表面表达的活动。因此，在这个小型R03提案中，实验的目的是通过评估这些重定向的preBCR复合物在体内的生物活性来建立这些发现。这将通过建立表达重定向Ig hc的转基因小鼠，并评估其支持B细胞发育的能力，以及在遗传prebcr缺乏和prebcr充足的小鼠中进行等位基因排斥的能力来实现。这一信息对于更好地理解在正常免疫发育和B细胞病理中决定受体活性的分子机制非常重要。该提案中的实验旨在了解被称为preBCR的关键分子如何控制B细胞的发育，B细胞是产生免疫反应所必需的抗体的细胞。基因上不能产生预bcr的人是严重的免疫缺陷。获得的信息需要更好地了解一些可以追溯到影响前bcr功能的突变的B细胞白血病的起源。