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

抗原非依赖性 IgG1 血管生成调节中性二态性的机制基础

基本信息

批准号：
10660051
负责人：
Bradley David Gelfand
金额：
$ 68.99万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660051
关键词：
Affinity Alzheimer&apos s Disease Angiogenesis Inhibitors Animal Model Animals Antibodies Antigens Beds Biological Blood Cells Blood Vessels Bone Marrow Cardiovascular system Cells Chemotaxis Choroidal Neovascularization Complement Coronary Arteriosclerosis Data Development Diabetic Retinopathy Disease Estradiol Estrogens Event Exhibits Exudative age-related macular degeneration Fc domain Female Four Core Genotypes Genes Genetic Glean Goals Gonadal Hormones Growth Guidelines Heart failure Hindlimb Hormonal Hormones Human IgG1 Immune Intervention Ischemia Knock-out Knowledge Macrophage Macular degeneration Malignant Neoplasms Mediating Mediator Modeling Morbidity - disease rate Mus Myocardial Ischemia Nature Pathologic Neovascularization Pathway interactions Peripheral arterial disease Physiological Plasma Ploidies Predisposition Prevalence Process Regulation Regulator Genes Risk Factors Role Severities Severity of illness Sex Bias Sex Chromosomes Sex Differences Signal Transduction Specimen Stroke System Testing Testosterone Therapeutic Tissues United States National Institutes of Health VEGFA gene Y Chromosome angiogenesis antigen binding chromosome Y loss dimorphism gain of function genotypic sex helicase human male improved outcome inhibiting antibody insight knock-down loss of function male mortality mosaic loss neovascularization novel personalized therapeutic prevent receptor response segregation sex sexual dimorphism

项目摘要

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.

项目摘要/摘要过量，异常或血管生成不足的疾病是世界上很大一部分的疾病发病率和死亡率。诸如外周动脉疾病，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，严重程度或最佳的风险因素中暴露了性二态性干预措施。尽管对这些差异的宽泛欣赏，但性别影响的机制血管状况尚不完全理解。例如，性别染色体完成的作用血管生成过程的定义不明。新证据表明，IgG1抗体调节的过程血管生成以抗原独立的方式（我们称为抗体依赖性细胞介导的血管抑制”或ADCAI）性二态性强烈，男性表现出更大的ADCAI 女性。在强大的初步数据的支持下，该项目的总体假设是ADCAI二态性由于Y染色体编码的基因DDX3Y的表达。我们将以三个特定的特定方式检验该假设目标。 1）我们将确定性别偏见因素的精确作用（性染色体完成和性腺分泌物）在ADCAI性二态性中。 2）我们将确定Y染色体编码的功能 DDX3Y是一种新型的ADCAI调节基因。 3）我们将量化人类细胞中对ADCAI的性别影响标本。总的来说，这些主题相关，但独立目标将建立新的基础和关于ADCAI的介体和后果的翻译相关知识。这些研究可能因此开放新的介入途径，以个性化的性别特定方式调节血管生成治疗应用。