Sexual dimorphism in antigen-independent angiogenesis inhibition of IgG1 antibodies

项目摘要 许多血管生成过度、异常或不足的疾病，如外周动脉疾病、新生血管性疾病、 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别差异。 二态性的风险因素，发病率和最佳干预措施。尽管人们普遍 认识到这些差异，促进血管内皮细胞性别差异的分子机制， 条件被低估了。我们实验室的研究证实，人IgG 1（和鼠等效物） IgG 2a/c）具有不依赖于抗原结合而发生的内在抗血管生成活性。相反， 活性是由于IgG 1的Fc结构域被高亲和力活化受体FcγRI识别， 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是一个进化上保守的，影响血管重塑的基本过程， 多种组织床和生理状态。根据美国国立卫生研究院关于性别作为生物学变量的指导方针， 我们最近做了几个惊人的观察，表明雌性动物和雌性来源的细胞表现出 与雄性相比，ADCAI显著降低。这些发现提出了一种有趣的可能性， ADCAI反应的差异可能导致血管重塑。然而，负责的机制 ADCAI的性别差异，以及ADCAI差异是否在人类中是保守的是未知的。这里我 建议进一步研究ADCAI中两性异形的机制。具体来说，我会 确定基因DDX 3 Y的作用，该基因被鉴定为ADCAI的潜在介质， 筛选Y染色体编码基因（Aim 1）。我还将调查性腺切除术对 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是保守的， 人源化Fc受体小鼠（Aim 3）。我的中心假设是ADCAI的两性异形是一种保守的 这一过程通过巨噬细胞中DDX 3 Y的表达而增强。这个项目将为我们提供新的视角， 性别之间的血管生成调节之间的对比，揭示了新的途径和目标，以调节 以更个性化的方式促进血管生成以改善治疗结果。

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.