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

• 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
• 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

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.

项目摘要 多种过量，异常或不足血管生成的疾病，例如周围动脉疾病，新生血管 与年龄有关的黄斑变性，实体瘤，周围动脉疾病和心力衰竭暴露 关于风险因素，事件和最佳干预措施的二态性。尽管宽度很大 确认这些差异，即促进血管性别差异的分子机制 理解条件。我们实验室的研究确定人IgG1（和鼠等效物 IgG2A/c）具有独立于抗原结合的固有抗血管生成活性。相反，这个 活性是由于高亲和力激活受体FcγRI识别IgG1的Fc结构域所致 巨噬细胞。我们将这种活性称为“抗体依赖性细胞介导的血管抑制”（ADCAI）。这些发现 表明ADCAI是一个进化保守的基本过程，会影响血管重塑 多个组织床和生理状态。由NIH的性别准则作为生物变量的指南提示， 我们最近进行了几次罢工观察，表明雌性动物和女性衍生细胞表现出 与男性相比，ADCAI明显减少。这些发现引起了性别分布的有趣可能性 在血管重塑中，ADCAI反应的差异可能会引起。但是，机制负责 对于ADCAI性别差异，以及在人类中是否存在ADCAI差异是未知的。在这里，我 提议进一步研究ADCAI性二态性的机制。具体来说，我会的 确定基因DDX3Y的作用，该基因被确定为无偏见的ADCAI的潜在介体 Y染色体编码基因的屏幕（AIM 1）。我还将调查性腺切除术对 ADCAI（AIM 2）。此外，我将测试ADCAI性别差异是否在人类巨噬细胞中保存下来，并且 人源化FC受体小鼠（AIM 3）。我的中心假设是，ADCAI的性二态性是保守的 通过在巨噬细胞中DDX3Y表达潜在的过程。这个项目将为 性别之间的血管生成调节之间的对比，揭示了新的途径和调节目标 血管生成以更个性化的方式改善治疗结果。