Genetic Dissection of the Pathophysiology of Polycystic Ovary Syndrome
多囊卵巢综合征病理生理学的基因剖析
基本信息
- 批准号:10739832
- 负责人:
- 金额:$ 16.79万
- 依托单位:
- 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:2023-09-01 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAsthmaAwardBioinformaticsBiologicalCardiometabolic DiseaseChildChildhoodClinicalCollaborationsComplexComputational BiologyComputing MethodologiesCuesDataData SetDiagnosisDiseaseDissectionEndocrineEndocrine System DiseasesEndocrinologyFemale infertilityFertilityFunctional disorderGene ExpressionGene set enrichment analysisGenesGeneticGenetic Predisposition to DiseaseGenetic RiskGenetic studyGoalsGonadotropinsGrowthHealthHealth Care CostsHeterogeneityHyperandrogenismIndividualInternationalLinkLipidsLongitudinal StudiesMentorshipMeta-AnalysisMetabolicMetabolic dysfunctionMethodsMolecularNational Institute of Child Health and Human DevelopmentOutcomeOvarianParentsPathogenesisPathway interactionsPediatric cohortPhenotypePhysiciansPhysiologicalPolycystic Ovary SyndromePositioning AttributePubertyRegulationReproductive EndocrinologyRiskRoleScientistSex BiasSpecificitySubgroupTestingTrainingVariantWeightWomanagedandrogen biosynthesisandrogenicbiobankcandidate identificationcardiometabolismcardiovascular disorder riskclinical carecohortexperiencefolliculogenesisgenetic risk factorgenetic variantgenome wide association studygenome-widegenomic locusinnovationinsightinsulin secretionmembermenmetabolomicsnovelovarian dysfunctionphenotypic datapolygenic risk scoreprecision medicineprepubertyreproductiverisk stratificationsexskillstherapeutic targettrait
项目摘要
PROJECT SUMMARY/ ABSTRACT
Polycystic ovary syndrome (PCOS) is a major health concern that affects up to 10% of all reproductive-aged
women and is the leading cause of female infertility. This complex, heterogeneous condition is associated with
ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction and incurs an estimated $8 billion
in annual U.S. healthcare costs. PCOS is associated with alterations in both ovarian factors (folliculogenesis,
gonadotropin secretion and action, ovarian androgen biosynthesis) and non-ovarian factors (insulin secretion
and action, weight and energy regulation). These contributing factors are all interconnected, and the inciting
causes of PCOS remains unknown. As a result, the clinical care of PCOS is currently confined to managing the
manifestations of PCOS rather than treating the underlying causes. The overall hypothesis for this study is that
PCOS arises from the perturbation of multiple metabolic and reproductive endocrine pathways, some of which
are shared and others distinct between women, men, and children. To test this hypothesis, this project will take
advantage of a recently completed genome wide-association study meta-analysis that has doubled the number
of genetic loci that influence PCOS risk. Because these genetic variants are present in all individuals, this
discovery enables examination of the phenotypic effects of genetic risk factors for PCOS in not just women but
also men and children. This project leverages the power of the UK Biobank, a cohort of nearly 400,000 adults
in the UK, and four pediatric cohorts, Avon Longitudinal Study of Parents and Children (N>6,000),
Copenhagen Studies on Asthma in Childhood (N>500), Project Viva (N>500), and the HOLBAEK Study
(N>4,000). In adults, genetic risk factors for PCOS will be assessed for sex-biased effects on cardiometabolic
and other outcomes and clustered with PCOS-related traits, and gene-set enrichment analysis will be used to
gain mechanistic insights into these groups of PCOS genetic risk factors. In children, genetic risk scores (i.e.,
estimated genetic susceptibility to PCOS) will be calculated and tested for associations with cardiometabolic
and androgenic traits as well as diverse metabolites. This proposal promises to implicate causal biological
mechanisms underlying the pathogenesis of PCOS and its associated features, which could allow for the
deconstruction of the causes of PCOS into distinct subgroups, and thereby pave the way for a precision-
medicine approach to the diagnosis, risk stratification, and treatment of PCOS in women and its associated
conditions in adults and children. Through this proposal, Dr. Zhu will attain new skills in advanced
computational genetic methods, experience in applying principles in computational biology and bioinformatics,
and a deep understanding of the impact of reproductive endocrinology on a variety of health conditions. The
K08 award will provide Dr. Zhu the critical training and mentorship to achieve her goal of becoming an
independent physician-scientist applying innovative computational methods to understand complex
reproductive endocrine disorders.
项目总结/摘要
多囊卵巢综合征(PCOS)是一个主要的健康问题,影响到10%的育龄妇女,
是女性不孕的主要原因。这种复杂的异质性疾病与
排卵功能障碍、高雄激素血症和心脏代谢功能障碍,估计造成80亿美元的损失
美国每年的医疗费用。多囊卵巢综合征与两种卵巢因子(卵泡发生,
促性腺激素分泌和作用、卵巢雄激素生物合成)和非卵巢因素(胰岛素分泌
以及动作、重量和能量调节)。这些促成因素都是相互关联的,
PCOS的病因尚不清楚。因此,PCOS的临床护理目前仅限于管理
多囊卵巢综合征的表现,而不是治疗的根本原因。这项研究的总体假设是,
多囊卵巢综合征是由多种代谢和生殖内分泌途径的干扰引起的,其中一些途径
女性、男性和儿童都有相同的性别,也有不同的性别。为了验证这一假设,该项目将
最近完成的一项基因组广泛关联研究荟萃分析的优势,
影响PCOS风险的基因位点。因为这些基因变异存在于所有个体中,
这一发现不仅使人们能够检查PCOS遗传风险因素的表型效应,
还有男人和孩子该项目利用了英国生物银行的力量,该银行拥有近40万成年人
在英国,和四个儿科队列,雅芳父母和儿童纵向研究(N>6,000),
哥本哈根儿童哮喘研究(N>500)、Viva项目(N>500)和霍尔贝克研究
(N> 4,000)。在成人中,将评估PCOS的遗传风险因素对心脏代谢的性别偏倚影响。
和其他结果,并与PCOS相关性状聚类,基因集富集分析将用于
获得对这些PCOS遗传风险因素的机械见解。在儿童中,遗传风险评分(即,
估计的PCOS遗传易感性)将被计算和测试与心脏代谢的关联。
和雄激素特征以及不同的代谢物。这一提议有望暗示因果生物学
PCOS的发病机制及其相关特征,这可能允许
将PCOS的原因解构为不同的亚组,从而为精确-
多囊卵巢综合征的诊断、危险分层和治疗的医学方法
成人和儿童的情况。通过这个建议,朱博士将获得先进的新技能,
计算遗传学方法,在计算生物学和生物信息学中应用原理的经验,
以及对生殖内分泌学对各种健康状况的影响的深刻理解。的
K 08奖将为朱博士提供关键的培训和指导,以实现她成为一名
独立物理学家兼科学家应用创新的计算方法来理解复杂的
生殖内分泌失调
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jia Zhu其他文献
Jia Zhu的其他文献
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{{ truncateString('Jia Zhu', 18)}}的其他基金
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
- 批准号:
10395951 - 财政年份:2021
- 资助金额:
$ 16.79万 - 项目类别:
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
- 批准号:
10230375 - 财政年份:2021
- 资助金额:
$ 16.79万 - 项目类别:
Modeling of human HSV infection: development of immune-competent 3D skin-on-chip with vascular perfusion
人类 HSV 感染建模:开发具有血管灌注功能的免疫活性 3D 皮肤芯片
- 批准号:
10328978 - 财政年份:2020
- 资助金额:
$ 16.79万 - 项目类别:
Modeling of human HSV infection: development of immune-competent 3D skin-on-chip with vascular perfusion
人类 HSV 感染建模:开发具有血管灌注功能的免疫活性 3D 皮肤芯片
- 批准号:
10555337 - 财政年份:2020
- 资助金额:
$ 16.79万 - 项目类别:
Mechanisms of Protective Local Immunity in Human Female Reproductive Tract
人类女性生殖道保护性局部免疫机制
- 批准号:
9220697 - 财政年份:2014
- 资助金额:
$ 16.79万 - 项目类别:
Mechanisms of Protective Local Immunity in Human Female Reproductive Tract
人类女性生殖道保护性局部免疫机制
- 批准号:
8705241 - 财政年份:2014
- 资助金额:
$ 16.79万 - 项目类别:
Mechanisms of Protective Local Immunity in Human Female Reproductive Tract
人类女性生殖道保护性局部免疫机制
- 批准号:
8816031 - 财政年份:2014
- 资助金额:
$ 16.79万 - 项目类别:
Mechanisms of CD8+ T cell Immune surveillance in human genital skin and mucosa af
CD8 T细胞对人类生殖器皮肤和粘膜免疫监测的机制
- 批准号:
8508374 - 财政年份:2012
- 资助金额:
$ 16.79万 - 项目类别:
Correlating HSV-2 Disease Severity with Tissue Resident CD8 T-cells
将 HSV-2 疾病严重程度与组织驻留 CD8 T 细胞相关联
- 批准号:
8696991 - 财政年份:
- 资助金额:
$ 16.79万 - 项目类别:
Correlating HSV-2 Disease Severity with Tissue Resident CD8 T-cells
将 HSV-2 疾病严重程度与组织驻留 CD8 T 细胞相关联
- 批准号:
8565777 - 财政年份:
- 资助金额:
$ 16.79万 - 项目类别:
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