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Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Men and Children

通过定义与男性和儿童 PCOS 遗传风险因素相关的表型来剖析 PCOS 生理学

基本信息

批准号：
10230375
负责人：
Jia Zhu
金额：
$ 7.49万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10230375
关键词：
Adrenal Glands Affect Androgens Asthma Biochemical Bioinformatics Biological Birth Boston Caring Child Childhood Classification Clinical Complex Computational Biology Counseling Data Denmark Development Diagnosis Disease Dyslipidemias Endocrinology Event Fellowship Fellowship Program Female First Degree Relative Foundations Functional disorder Future Genetic Genetic Predisposition to Disease Genetic Risk Genetic Techniques Genetic study Goals Gonadotropins Grant Health Health Care Costs Human Genetics Hyperandrogenism Individual Institutes Insulin Resistance Lead Learning Longitudinal Studies Male Pattern Baldness Mentors Mothers Obesity Ovarian Parents Pathogenesis Pathway interactions Pediatric Hospitals Phenotype Physiological Physiology Polycystic Ovary Syndrome Production Regulation Reproduction Reproductive Endocrinology Research Personnel Resources Risk Risk Factors Testing Training Translational Research Triad Acrylic Resin Weight Woman aged androgen biosynthesis biobank cardiometabolic risk cardiometabolism career clinical care clinical practice cohort folliculogenesis genetic risk factor genetic variant genome wide association study genomic data girls high body mass index insight insulin secretion men metabolic phenotype ovarian dysfunction phenome phenotypic data population based premature adrenarche prepuberty reproductive skills targeted treatment

项目摘要

PROJECT SUMMARY/ ABSTRACT Polycystic ovarian syndrome (PCOS) is a major health concern that affects up to 10% of all reproductive-aged women. This complex, heterogeneous condition is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction and incurs an estimated $4.3 billion in annual U.S. healthcare costs. Despite extensive physiologic and genetic studies, the treatment of PCOS remains limited by an incomplete understanding of the pathophysiology of the disorder. Existing evidence suggests that PCOS is associated with both ovarian-related factors (gonadotropin secretion and action, folliculogenesis, androgen biosynthesis) and ovarian-independent factors (adrenal androgen biosynthesis, insulin secretion and action, weight and energy regulation), but which of these are the inciting events and which are the secondary consequences are unknown. The overall hypothesis for this study is that PCOS is not always primarily a disorder of female reproduction, but rather can be primarily a condition of hyperandrogenism and/or cardiometabolic dysregulation, with ovarian dysfunction as a secondary consequence. To test this hypothesis, this project will take advantage of a recent genome wide-association study (GWAS) that discovered numerous genetic variants that influence PCOS risk. Because these genetic variants are present in all individuals, this discovery provides a unique opportunity to study the phenotypic effects of genetic risk factors for PCOS in men and prepubertal children without the influence of ovarian factors. This project leverages the power of the UK Biobank, a population-based cohort of 176,367 unrelated men in the UK, and two longitudinal pediatric birth cohorts, the Copenhagen Studies on Asthma in Childhood (COPSAC) in Denmark with 558 children and the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK with 6,791 children. Genetic risk scores (i.e. estimated genetic susceptibility to PCOS) will be calculated in men from the UK Biobank and prepubertal children from COPSAC and ALSPAC and tested for associations with hyperandrogenic and cardiometabolic phenotypes. Characterizing the phenotypes in men and children who carry genetic risk factors for PCOS will provide a starting point for identifying specific biological pathways underlying the pathogenesis of PCOS, allow for the future development of targeted therapies for PCOS, and deepen our understanding of pediatric manifestations of genetic risk factors for PCOS. The fellowship training plan consists of a co-mentoring team composed of Dr. Joel Hirschhorn and Dr. Yee-Ming Chan at the Broad Institute and the Division of Endocrinology at Boston Children’s Hospital (BCH). Dr. Hirschhorn’s lab and the Broad Institute will provide Dr. Zhu with extensive training in human genetics of polygenic disease and computational biology and bioinformatics. Dr. Chan’s lab will provide Dr. Zhu with training in scientific and clinical pediatric reproductive endocrinology. The pediatric endocrinology fellowship program at BCH will provide Dr. Zhu with exceptional training in the clinical practice of pediatric endocrinology.

项目摘要/摘要