Sunday, May 18, 2025
5/18/2025
Mechanistic basis of sexual dimorphism in antigen-independent IgG1 angiogenesis regulation - 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.
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