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

基本信息

批准号：
8607987
负责人：
Coleen A McNamara
金额：
$ 37.73万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607987
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 Intervention 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 public health relevance receptor expression

项目摘要

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.

描述（由申请人提供）：动脉粥样硬化是一种进行性炎症过程，导致大动脉中形成斑块。关于巨噬细胞和 T 细胞向血管壁的募集及其在斑块进展中的作用，人们已经了解很多。在人类和动物动脉粥样硬化模型的整个疾病过程中，斑块和外膜中都发现了 B 细胞和浆细胞，并且在小鼠模型中，整体 B 细胞缺乏已被证明会促进动脉粥样硬化。然而，调节主动脉 B 细胞归巢的因素以及这些因素的调节对动脉粥样硬化形成的影响仍然未知。通过细胞培养和动物研究，我们确定了螺旋-环-螺旋因子 (HLH) Id3 作为一种新型动脉粥样硬化保护因子，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 B 淋巴细胞至关重要。介导的动脉粥样硬化保护。此外，我们最近在人类 ID3 基因中发现了一个单核苷酸多态性 (SNP)，它编码一种 Id3 蛋白，其作为 bHLH E 蛋白 E12 的二聚化伴侣和显性失活抑制剂的功能减弱。该 SNP 与人类颈动脉内膜内侧厚度 (cIMT) 相关。具有编码 Id3 蛋白且 Id3:E12 二聚化减弱的次要等位基因的人类 cIMT（亚临床动脉粥样硬化标志物）增加。将小鼠、人类和生化数据结合在一起，使我们推测 E12 活性的丧失通过增加趋化因子受体表达和增加小鼠 B 淋巴细胞的动脉归巢来促进动脉粥样硬化保护，并且人类 ID3 基因 rs11574 (Id3105T) 的多态性导致人 E12 活性拮抗作用的降低可以抑制趋化因子受体的表达，从而减少趋化性和动脉归巢人类 B 淋巴细胞。鉴定 E12 作为主动脉 B 淋巴细胞归巢和 B 淋巴细胞介导的动脉粥样硬化保护的关键调节因子，不仅对于进一步研究以拓宽我们对动脉粥样硬化形成免疫调节的理解范式很重要，而且还可能导致新生物标志物（ID3 基因）的鉴定。多态性）和促进人类动脉粥样硬化保护的创新策略。基于我们令人信服的初步数据并利用新型试剂，我们提出以下目标来解决我们的假设：目标 1：确定 E12 表达的调节是否调节 B 淋巴细胞中的 CCR6 表面蛋白表达和趋化性。目标 2：确定携带与 E12 拮抗作用减弱和人类 cIMT 增加相关的 Id3 多态性的 B 淋巴细胞是否会降低 CCR6 表达并降低 B 淋巴细胞趋化性。目标 3：确定 E12 在体内对主动脉 B 细胞归巢和动脉粥样硬化保护的作用，并确定 Id3 rs11574 的多态性是否会改变主动脉 B 细胞归巢。