Sexual dimorphism in antigen-independent angiogenesis inhibition of IgG1 antibodies

IgG1 抗体的抗原非依赖性血管生成抑制中的性别二态性

基本信息

批准号：
10705615
负责人：
Dionne Alexis Argyle
金额：
$ 3.66万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705615
关键词：
Address Adult Affect Affinity Age related macular degeneration Angiogenesis Inhibition Angiogenesis Inhibitors Animal Model Animals Antibodies Antigens Arthritis Beds Binding Biochemical Biological Biological Assay Biological Models Birth Blindness Blood Vessels Bone Marrow CBL gene Cardiovascular Diseases Categories Cell model Cells Characteristics Chemotaxis Code Coronary Arteriosclerosis Disease Disparity Equilibrium Estrogens Exhibits Exudative age-related macular degeneration Fc Receptor Fc domain Female Genes Germ Cells Goals Guidelines Heart failure Homeostasis Hormonal Human IgG Receptors Incidence Inflammatory Bowel Diseases Intervention Ischemic Stroke Knowledge Link Macrophage Malignant Neoplasms Mediating Mediator Medical Modeling Molecular Mus Outcome Pathogenesis Pathologic Neovascularization Pathway interactions Pattern Peripheral arterial disease Phosphorylation Physiological Play Policies Process Proteins Publishing Regulation Reporting Research Risk Factors Role Severities Sex Bias Sex Chromosomes Sex Differences Signal Transduction Solid Neoplasm Testing Testosterone Therapeutic Agents Tissues Transgenes Ubiquitination United States National Institutes of Health Vascular Endothelial Growth Factor Receptor-1 Vascular remodeling Woman Y Chromosome age related angiogenesis antigen binding diabetic ulcer helicase human male improved knockout gene male men mouse model personalized approach receptor response sex sex disparity sexual dimorphism skin disorder therapy outcome treatment response vascular abnormality

项目摘要

PROJECT SUMMARY Many diseases of excess, abnormal, or insufficient angiogenesis such as peripheral artery disease, neovascular age-related macular degeneration, solid tumors, peripheral artery disease, and heart failure exhibit sexual dimorphism with respect to risk factors, incidence, and optimal interventions. Despite widespread acknowledgement of these disparities, the molecular mechanisms that promote sex differences in vascular conditions are understudied. Studies from our lab established that human IgG1 (and the murine equivalents IgG2a/c) possess intrinsic anti-angiogenic activity which occurs independently of antigen binding. Instead, this activity is due to recognition of the Fc domain of IgG1 by the high-affinity activating receptor FcγRI in macrophages. We term this activity “antibody-dependent cell-mediated angioinhibition” (ADCAI). These findings suggest that ADCAI is an evolutionarily conserved, fundamental process that affects vascular remodeling in multiple tissue beds and physiologic states. Prompted by the NIH's Guidelines on Sex as a Biological Variable, we recently made several striking observations suggesting that female animals and female-derived cells exhibit markedly reduced ADCAI compared to males. These findings raise the intriguing possibility that sex disparities in vascular remodeling may arise from differences in ADCAI responses. However, the mechanisms responsible for ADCAI sex differences, and whether ADCAI disparities are conserved in humans are unknown. Here, I propose to further investigate the mechanisms underlying sexual dimorphism in ADCAI. Specifically, I will determine the role of the gene DDX3Y, which was identified as a potential mediator of ADCAI in an unbiased screen of Y chromosome encoded genes (Aim 1). I will also investigate the affects that gonadectomies have on ADCAI (Aim 2). In addition, I will test whether ADCAI sex differences are conserved in human macrophages and humanized Fc receptor mice (Aim 3). My central hypothesis is that sexual dimorphism of ADCAI is a conserved process that is potentiated by expression of DDX3Y in macrophages. This project will shed new light on the contrasts between the angiogenesis regulation between sexes, revealing new pathways and targets to modulate angiogenesis in a more personalized manner to improve therapeutic outcomes.

项目概要许多血管生成过多、异常或不足的疾病，例如外周动脉疾病、新生血管疾病年龄相关性黄斑变性、实体瘤、外周动脉疾病和心力衰竭表现出性尽管采取了广泛的措施，但风险因素、发病率和最佳干预措施仍存在二态性。承认这些差异，促进血管性别差异的分子机制我们实验室的研究表明，人类 IgG1（以及小鼠的等效物） IgG2a/c) 具有内在的抗血管生成活性，其发生独立于抗原结合。活性是由于高亲和力激活受体 FcγRI 识别 IgG1 的 Fc 结构域所致我们将这种活性称为“抗体依赖性细胞介导的血管抑制”（ADCAI）。表明 ADCAI 是一个进化上保守的基本过程，影响血管重塑根据美国国立卫生研究院关于性别作为生物变量的指南的提示，我们最近做了一些惊人的观察，表明雌性动物和雌性衍生细胞表现出与男性相比，ADCAI 显着降低。这些发现提出了性别差异这一有趣的可能性。血管重塑的差异可能是由 ADCAI 反应的差异引起的，但其机制却不同。对于 ADCAI 性别差异，以及 ADCAI 差异在人类中是否保守尚不清楚。建议进一步研究 ADCAI 性别二态性的机制。具体来说，我将。确定基因 DDX3Y 的作用，该基因被确定为 ADCAI 在无偏倚中的潜在介质 Y 染色体编码基因的筛选（目标 1）我还将研究性腺切除术的影响。 ADCAI（目标 2）此外，我将测试 ADCAI 性别差异是否在人类巨噬细胞中保守。人源化 Fc 受体小鼠（目标 3）我的中心假设是 ADCAI 的性别二态性是保守的。巨噬细胞中 DDX3Y 的表达增强了这一过程，该项目将为这一过程提供新的线索。性别之间血管生成调节的对比，揭示了新的调节途径和靶点以更加个性化的方式进行血管生成，以改善治疗结果。