Sexual dimorphism in antigen-independent angiogenesis inhibition of IgG1 antibodies

项目总结 许多血管生成过多、异常或不足的疾病，如外周动脉疾病、新生血管 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为性 在风险因素、发病率和最佳干预措施方面的二形性。尽管广泛存在 认识到这些差异，促进血管性别差异的分子机制 对条件的研究还不够深入。我们实验室的研究证实，人IgG1(和小鼠的等价物) IgG2a/c)具有不依赖于抗原结合的内在抗血管生成活性。相反，这是 其活性是由于高亲和力激活受体FcγRI识别IgG1Fc结构域。 巨噬细胞。我们将这种活性称为“抗体依赖细胞介导的血管抑制”(ADCAI)。这些发现 提示ADCA1是一个进化保守的基本过程，影响血管重构。 多个组织床和生理状态。在美国国立卫生研究院将性作为生物变量的指导方针的推动下， 我们最近进行了几项惊人的观察，表明雌性动物和雌性来源的细胞 与男性相比，ADCAI显著降低。这些发现提出了一种有趣的可能性，即性别差异 血管重塑方面的差异可能源于ADCAI反应的不同。然而，负责的机制 至于ADCAI的性别差异，以及ADCAI差异是否在人类中保守，目前尚不清楚。在这里，我 建议进一步研究ADCAI性二型性的发病机制。具体来说，我会 确定基因DDX3Y的作用，该基因被认为是ADCI的一个潜在的中介因子 Y染色体编码基因的筛选(目标1)。我还会调查性腺切除术对 ADCAI(目标2)。此外，我将测试ADCAI性别差异是否在人类巨噬细胞和 人源化Fc受体小鼠(目标3)。我的中心假设是ADCAI性二型性是一种保守的 巨噬细胞中DDX3Y表达增强的过程。这一项目将使人们对 性别间血管生成调控的对比，揭示新的调控途径和靶点 以更个性化的方式进行血管生成，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.