Mechanistic basis of sexual dimorphism in antigen-independent IgG1 angiogenesis regulation

项目摘要/摘要 血管生成过多、异常或不足的疾病造成了世界上很大一部分 发病率和死亡率。外周动脉疾病、黄斑变性、冠状动脉 疾病、中风和心力衰竭在风险因素、患病率、严重程度或最佳状态方面表现出性别二型性 干预措施。尽管这些差异得到了广泛的认可，但性别影响的机制 人们对血管状况的了解还不完全。例如，性染色体补体在 血管生成过程的定义并不明确。新证据表明，IgG1抗体调节的过程 以不依赖于抗原的方式(我们称之为“抗体依赖细胞介导”)的血管生成 血管抑制“或ADCAI)具有很强的性别二型性，与男性相比，男性表现出更大的ADAI 女性。在稳健的初步数据支持下，本项目的总体假设是ADCAI二型性出现 由于Y染色体编码基因DDX3Y的表达。我们将从三个具体的方面来检验这一假设 目标。1)我们将确定性别偏见因素(性染色体互补和性腺)的确切作用 分泌物)在ADCAI性二型性。2)我们将确定Y染色体编码的功能 DDX3Y是一个新的ADCAI调控基因。3)我们将量化性别对人类细胞ADAI的影响，并 标本。总的来说，这些主题相关但独立的目标将建立新的基础和 关于ADCAI的调解人和后果的翻译相关知识。因此，这些研究可能 开辟新的介入途径，以个性化、性别特异性的方式调节不同性别的血管生成 治疗应用。

PROJECT ABSTRACT/SUMMARY Diseases of excess, aberrant, or insufficient angiogenesis are responsible for a large portion of the world's morbidity and mortality. Conditions such as peripheral artery disease, macular degeneration, coronary artery disease, stroke, and heart failure exhibit sexual dimorphism in risk factors, prevalence, severity, or optimal interventions. Despite widespread appreciation of these differences, the mechanisms by which sex influences vascular conditions are incompletely understood. For example, the role of sex chromosomal complement in angiogenic processes is ill defined. New evidence suggests that the process by which IgG1 antibodies regulate angiogenesis in an antigen-independent manner (which we term “antibody-dependent cell-mediated angioinhibition” or ADCAI) is strongly sexually dimorphic, with males exhibiting far greater ADCAI compared to females. Supported by robust preliminary data, the overall hypothesis of this project is ADCAI dimorphism arises due to expression of the Y chromosome-encoded gene DDX3Y. We will test this hypothesis in three specific aims. 1) We will establish the precise roles of sex-biasing factors (sex chromosome complement and gonadal secretions) in ADCAI sexual dimorphism. 2) We will determine the function of the Y chromosome-encoded DDX3Y as a novel ADCAI regulatory gene. 3) We will quantify the sex effect on ADCAI in human cells and specimens. Collectively, these thematically related, but independent aims will establish new foundational and translationally relevant knowledge about the mediators and consequences of ADCAI. These studies may thereby open new interventional avenues to modulate angiogenesis in a personalized, sex-specific manner for diverse therapeutic applications.