Genetic Regulation of B Lymphocyte Aortic Homing and Atheroprotection

B 淋巴细胞主动脉归巢和动脉粥样硬化的基因调控

• 批准号: 8083888
• 负责人: Coleen A McNamara
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8083888
• 关键词: Address; Adoptive Transfer; Alleles; Animal Model; Animals; Apolipoprotein E; Arteries; Atherosclerosis; Attenuated; B-Lymphocytes; Biochemical; Biological Markers; CCL20 gene; CCR6 gene; CXCR4 gene; Cell Culture Techniques; Cells; Chemotaxis; Data; Defect; Development; Diet; Dimerization; Disease; Dominant-Negative Mutation; E protein; Early treatment; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Hand; Helix-Turn-Helix Motifs; Homing; Human; Immune; Immunity; Individual; Inflammatory; Intervention; Knockout Mice; Lead; Ligands; Link; Medial; Mediating; Membrane Proteins; Messenger RNA; Minor; Modeling; Molecular; Morbidity - disease rate; Mus; Pathway interactions; Patients; Plasma Cells; Process; Proteins; Public Health; Reagent; Regulation; Repression; Risk; Risk Factors; Risk Marker; Role; Single Nucleotide Polymorphism; T-Lymphocyte; Thick; Tunica Adventitia; atherogenesis; atheroprotective; attenuation; base; burden of illness; chemokine receptor; humoral immunity deficiency; in vivo; inhibitor/antagonist; innovation; mRNA Expression; macrophage; mortality; mouse model; novel; novel marker; promoter; protein expression; receptor expression

DESCRIPTION (provided by applicant): Atherosclerosis is a progressive, inflammatory process leading to plaque formation in large arteries. Much is known about recruitment of macrophages and T cells to the vessel wall and their role in plaque progression. B cells and plasma cells have been identified in plaque and adventitia in humans and animal models of atherosclerosis throughout the course of disease and global B cell deficiency has been shown to promote atherosclerosis in murine models. Yet, the factors that regulate aortic B cell homing and the impact of modulation of these factors on atherogenesis, remain unknown. Using cell culture and animal studies, we have identified the helix-loop-helix factor (HLH), Id3, as a novel atheroprotective factor that regulates expression of chemokine receptors and aortic homing of B lymphocytes and demonstrated that Id3 was essential for B lymphocyte-mediated atheroprotection. In addition, we have recently identified a single nucleotide polymorphism (SNP) in the human ID3 gene that encodes an Id3 protein with attenuated function as a dimerization partner and dominant negative inhibitor of the bHLH E-protein, E12. This SNP is associated with carotid intima medial thickness (cIMT) in humans. Humans with the minor allele encoding an Id3 protein with attenuated Id3:E12 dimerization have an increase in cIMT (marker of subclinical atherosclerosis). Taking the mouse, human and biochemical data together, leads us to hypothesize that loss of E12 activity promotes atheroprotection through increased chemokine receptor expression and increased arterial homing of B lymphocytes in mice and that polymorphism in the human ID3 gene at rs11574 (Id3105T) resulting in reduced antagonism of human E12 activity allows repression of chemokine receptor expression, reducing chemotaxis and arterial homing of human B lymphocytes. Identification of E12 as a critical regulator of aortic B lymphocyte homing and B lymphocyte-mediated atheroprotection is not only important for further studies to broaden the paradigm of our understanding of immune regulation of atherogenesis, but may also lead to identification of novel biomarkers (ID3 gene polymorphism) and innovative strategies to promote atheroprotection in humans. Based on our compelling preliminary data and utilizing novel reagents, we propose the following aims to address our hypothesis: Aim 1: Determine if modulation of E12 expression regulates CCR6 surface protein expression and chemotaxis in B lymphocytes. Aim 2: Determine if B lymphocytes harboring the Id3 polymorphism associated with attenuated antagonism of E12 and increased cIMT in humans have reduced CCR6 expression and reduced B lymphocyte chemotaxis. Aim 3: Determine the role of E12 on aortic B cell homing and atheroprotection in vivo and determine if polymorphism in Id3 at rs11574 alters aortic B cell homing. PUBLIC HEALTH RELEVANCE: Atherosclerosis is a public health issue of considerable importance due to the magnitude of the problem and the associated morbidity and mortality. Traditional atherosclerotic risk factors are not always predictive of disease burden in patients. Identification of novel markers of atherosclerosis risk based on loss of protective immunity has the potential to broaden the paradigm of atherosclerosis development and lead to early, innovative, intervention strategies to reduce atherosclerosis through enhancing immune protection. We have identified a novel atheroprotective pathway in mice mediated by immune cells called B lymphocytes, and discovered molecular (Id3) and cellular (CCR6 and CXCR4) factors in B lymphocytes mediating this effect. In this application, we propose to further dissect out the molecular pathways that regulate B lymphocyte- mediated atheroprotection in mice and determine if polymorphism in the human ID3 gene at rs11574 results in alterations of this important molecular pathway as a link to potential atheroprotective mechanisms in humans. Results may not only identify, original and unconventional risk markers, but may also lay the groundwork for bold and creative approaches to bolster immune protection from atherosclerosis in humans.

描述（由申请人提供）：动脉粥样硬化是一种进行性炎症过程，导致大动脉形成牙菌斑。关于将巨噬细胞和T细胞募集到血管壁及其在牙菌斑进展中的作用的知之甚少。在整个疾病过程中，已经在人类的斑块和斑块中鉴定了B细胞和浆细胞，并且已证明全球B细胞缺乏症可以促进鼠模型中的动脉粥样硬化。然而，调节主动脉B细胞归纳的因素以及这些因素对动脉粥样硬化的影响的影响仍然未知。使用细胞培养和动物研究，我们已经确定了螺旋 - 环螺旋因子（HLH），ID3是一种新型的动脉保护因子，可调节趋化因子受体的表达和B淋巴细胞的主动脉归巢，并证明ID3对于双淋巴细胞介导的介导的动脉动脉动脉粥样硬化至关重要。此外，我们最近在人ID3基因中确定了单个核苷酸多态性（SNP），该基因编码具有降低功能的ID3蛋白作为二聚伴侣和BHLH E蛋白E12的显性负抑制剂。该SNP与人类的颈动脉内膜厚度（CIMT）有关。次要等位基因编码ID3蛋白质的人类具有减弱ID3：E12二聚化的人（亚临床动脉粥样硬化的标志）。将小鼠，人类和生物化学数据共同完成，导致我们假设E12活性的丧失通过增加的趋化因子受体表达并增加小鼠B淋巴细胞的动脉归位，从而促进了动脉毒化，并且在RS11574（ID3105T）中的人ID3基因中，人ID3基因中的多态性促进了人ID3基因（ID3105T）的作用。减少人类B淋巴细胞的趋化性和动脉归位。将E12鉴定为主动脉B淋巴细胞寄养和B淋巴细胞介导的动脉保护剂的关键调节剂，不仅对于进一步的研究来扩大我们对动脉粥样硬化的免疫调节的范式的重要性，而且还可能导致对新型生物标志物（ID3 Gene Polymphistiss and Inservations in norlaverative seartive intherive s of any of and of ant a anthoverations）的范围。基于我们引人注目的初步数据并利用新的试剂，我们提出以下目的旨在解决我们的假设：目标1：确定E12表达的调节是否调节B淋巴细胞中CCR6表面蛋白表达和趋化性。目标2：确定具有与E12拮抗作用相关的ID3多态性和人类CIMT增加的B淋巴细胞是否降低了CCR6表达并降低了B淋巴细胞趋化性。 AIM 3：确定E12在体内主动脉B细胞归巢和动脉保护作用上的作用，并确定在RS11574时ID3中的多态性是否改变了主动脉B细胞的归因。 公共卫生相关性：由于问题的幅度以及相关的发病率和死亡率，动脉粥样硬化是一个非常重要的公共卫生问题。传统的动脉粥样硬化危险因素并不总是预测患者疾病负担。基于保护性免疫的丧失，对动脉粥样硬化风险的新标志物的鉴定有可能扩大动脉粥样硬化发育的范式，并导致早期，创新的干预策略，从而通过增强免疫保护来减少动脉粥样硬化。我们已经确定了由称为B淋巴细胞的免疫细胞介导的小鼠中的一种新型动脉保护途径，并发现了介导这种作用的B淋巴细胞中的分子（ID3）和细胞（CCR6和CXCR4）因子。在此应用中，我们建议进一步剖析调节小鼠中B淋巴细胞介导的动脉保护的分子途径，并确定在RS11574的人ID3基因中的多态性是否导致这种重要分子途径的改变，作为与人类潜在的动脉保护机制的联系。结果可能不仅可以识别原始和非常规的风险标记，而且还可能为大胆而创造性的方法奠定了基础，以增强人类动脉粥样硬化的免疫保护。