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

• 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
• 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' 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

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/总结 血管生成过度、异常或不足的疾病是造成世界上大部分血管生成障碍的原因。 发病率和死亡率。周围动脉疾病、黄斑变性、冠状动脉疾病等疾病 疾病、中风和心力衰竭在危险因素、患病率、严重程度或最佳治疗方面表现出性别二态性。 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 对血管疾病的了解还不完全。例如，性染色体补体在 血管生成过程不明确。新的证据表明IgG 1抗体调节的过程 以抗原非依赖性方式（我们称之为“抗体依赖性细胞介导的血管生成 血管抑制”或ADCAI）是强烈的性二态性，与男性相比，男性表现出更大的ADCAI。 女性在强大的初步数据的支持下，本项目的总体假设是ADCAI二态性出现 由于Y染色体编码基因DDX 3 Y的表达。我们将在三个具体的实验中验证这一假设。 目标。1)我们将建立性别偏向因素（性染色体补体和性腺激素）的精确作用。 分泌物）在ADCAI性二型性。2)我们将确定Y染色体编码的 DDX 3 Y是一个新的ADCAI调控基因。3)我们将量化人类细胞中性别对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的介质和后果的相关知识。这些研究可以 开辟新的干预途径，以个性化，性别特异性的方式调节血管生成， 治疗应用。