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

项目摘要/总结 血管生成过多、异常或不足的疾病是造成世界上很大一部分血管生成疾病的原因。 发病率和死亡率。外周动脉疾病、黄斑变性、冠状动脉等疾病 疾病、中风和心力衰竭在危险因素、患病率、严重程度或最佳水平方面表现出性别二态性 干预措施。尽管人们广泛认识到这些差异，但性别影响的机制 血管状况尚不完全了解。例如，性染色体补体在 血管生成过程尚不明确。新证据表明 IgG1 抗体调节的过程 以不依赖于抗原的方式进行血管生成（我们称之为“抗体依赖性细胞介导的”） 血管抑制”或 ADCAI）具有强烈的性别二态性，与男性相比，男性表现出更大的 ADCAI 女性。在可靠的初步数据的支持下，该项目的总体假设是 ADCAI 二态性出现 由于 Y 染色体编码基因 DDX3Y 的表达。我们将在三个具体方面检验这一假设 目标。 1）我们将建立性别偏见因素（性染色体补体和性腺）的精确作用 ADCAI 性二态性中的分泌物）。 2) 我们将确定Y染色体编码的功能 DDX3Y 作为一种新型 ADCAI 调控基因。 3）我们将量化性别对人类细胞中ADCAI的影响， 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 的中介因素和后果的翻译相关知识。这些研究可能因此 开辟新的介入途径，以个性化、针对不同性别的方式调节血管生成 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.