Mechanisms and Fetal Origins Underlying Gonadal Germ Cell Tumor-AWARDED

性腺生殖细胞肿瘤的机制和胎儿起源-获奖

基本信息

批准号：
10622303
负责人：
Louise Clare Pyle
金额：
$ 21.68万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-14 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622303
关键词：
ATAC-seq Address Adult Alleles Anxiety Atypia Award Basic Science Bioinformatics Biological Process CHEK2 gene CRISPR/Cas technology Cancer Biology Cancer Remission Cardiovascular Diseases Cell model Cells Child Childhood Chromatin Clinical Complex Congenital Abnormality Copy Number Polymorphism Cryptorchidism Data Data Set Development Diagnosis Doctor of Philosophy Electronic Health Record Epigenetic Process Family Fetal Development Five-Year Plans Funding Future GAB2 gene Gene Expression Genes Genetic Genetic Predisposition to Disease Genital Genitalia Genome Genomics Genotype Germ Cells Germ cell tumor Goals Gonadal Disorders Gonadal structure Heritability Human Human Genetics Hypogonadism Hypospadias Impairment Individual International Knock-out Knowledge Malignant Neoplasms Mental Depression Mentors Mentorship Modeling Molecular Biology Molecular Epidemiology Morbidity - disease rate Mutation Oncology Pathway interactions Pediatric Hospitals Pennsylvania Philadelphia Physicians Population Study Predisposition Prevention Prevention strategy Regulation Research Research Personnel Research Project Grants Resources Risk Role Scientist Signal Transduction Structure of primordial sex cell Susceptibility Gene Testicular Germ Cell Tumor Testing Training Translational Research Universities Work aged ambiguous genitalia base biobank career causal variant conventional therapy design epidemiology study exome sequencing fetal genetic approach genome wide association study genomic data genomic variation gonad development human model human tissue improved induced pluripotent stem cell induced pluripotent stem cell technology innovation lifetime risk medical specialties men phenotypic data precision cancer prevention precision genetics precision medicine recruit risk variant skills stem cell biology tool transcriptome sequencing treatment strategy tumor years of life lost

项目摘要

PROJECT SUMMARY Testicular germ cell tumor (TGCT) is the most common cancer in men 15-45 years old, and among adult cancers results in the greatest years of life lost. Among children with gonadal/genital atypia (the applicant’s specialty), the lifetime risk of gonadal germ cell tumor is up to 50%. However, which genes predispose to these tumors, and thus would be targets for precision-medicine-based prevention and treatment approaches, remain mostly unknown. The applicant recently identified both the first Mendelian gene predisposing to TGCT, and new genome-wide association hits for TGCT. In the research project proposed here we will determine the mechanisms through which these genomic variations impair cell-autonomous germ cell specification and/or epigenetic reprogramming (Aim 1) and gonadal niche formation (Aim 2). I hypothesize that alleles which predispose to TGCT impair specific stages of germ cell development. These aims will be accomplished using innovative modeling of human germ cells with induced pluripotent stem cells (iPSCs), and a genetic biobank of ~100,000 children with phenotypic data by which to identify those with gonadal/genital atypia and risk for TGCT. This data will advance our understanding of TGCT predisposition and initiation, and will expand our knowledge of typical gonadal development. The results from this study will provide rationale for future precision cancer prevention and treatment strategies. This proposal describes a five-year plan for the applicant to develop an independent research career as an academic oncogeneticist focused on germ cell tumor predisposition and prevention. The applicant, Dr. Pyle, is an attending pediatric geneticist at Children’s Hospital of Philadelphia (CHOP) with PhD training in basic molecular biology and precision medicine. Her research focuses on identifying germline genetic features that predispose to TGCT, and understanding their mechanisms of action. The goals for this award are to further develop the skills required for a successful career as an independent investigator, including expertise in bioinformatic analysis and handling of large genetic and phenotypic data sets, modeling of human tissue with iPSCs, and cancer biology. The mentors for this award, Drs. Hakon Hakonarson and Katherine L. Nathanson, are internationally recognized leaders in pediatric genetic discovery and genetic predisposition to cancer, respectively. Dr. Pyle will be supported by a mentorship committee comprising leaders in oncology, statistical genetics, and gonadal development. Dr. Pyle will also benefit from the unparalleled resources and mentorship available at CHOP and the University of Pennsylvania.

项目概要睾丸生殖细胞肿瘤 (TGCT) 是 15-45 岁男性和成年人中最常见的癌症癌症导致患有性腺/生殖器异型性的儿童（申请人的）寿命缩短。专业），性腺生殖细胞肿瘤的终生风险高达 50%，然而，哪些基因易患这些肿瘤。肿瘤，因此将成为基于精准医学的预防和治疗方法的目标，仍然申请人最近发现了第一个易患 TGCT 的孟德尔基因，以及 TGCT 的新全基因组关联命中在此提出的研究项目中，我们将确定这些基因组变异损害细胞自主生殖细胞规范的机制和/或表观遗传重编程（目标 1）和性腺生态位形成（目标 2）。 TGCT 易损害生殖细胞发育的特定阶段，这些目标将通过使用来实现。使用诱导多能干细胞（iPSC）对人类生殖细胞进行创新建模，以及基因生物库约 100,000 名儿童的表型数据可用于识别性腺/生殖器异型性和患病风险这些数据将增进我们对 TGCT 倾向和启动的理解，并将扩大我们的研究范围。这项研究的结果将为未来的精确性提供依据。该提案描述了申请人的五年计划。作为专注于生殖细胞肿瘤的学术肿瘤遗传学家发展独立的研究生涯申请人 Pyle 博士是儿童医院的主治儿科遗传学家。费城 (CHOP) 博士，接受基础分子生物学和精准医学研究。专注于识别易受 TGCT 影响的种系遗传特征，并了解其特征该奖项的目标是进一步培养成功职业生涯所需的技能。作为一名独立研究者，包括生物信息分析和处理大型遗传和生物信息学方面的专业知识表型数据集、iPSC 人体组织建模以及癌症生物学该奖项的导师， Hakon Hakonarson 博士和 Katherine L. Nathanson 博士是国际公认的儿科领导者派尔博士将分别获得遗传发现和癌症遗传倾向的支持。导师委员会由肿瘤学、统计遗传学和性腺发育领域的领导者组成。还将受益于 CHOP 和大学提供的无与伦比的资源和指导宾夕法尼亚州。