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

• 批准号: 10415857
• 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
• 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/10415857
• 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; Qualifying; Regulation; Research; Research Personnel; Research Project Grants; Resources; Risk; Role; Scientist; Signal Transduction; Specific qualifier value; Structure of primordial sex cell; Susceptibility Gene; Testicular Germ Cell Tumor; Testing; Training; Translational Research; Universities; Work; aged; ambiguous genitalia; 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

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.

项目摘要 有证明的生殖细胞肿瘤（TGCT）是15-45岁的男性中最常见的癌症，在成年人中 癌症导致生命中最大的几年丧失。在性腺/生殖器异型的儿童中（申请人的 专业），性腺生殖细胞肿瘤的寿命风险高达50％。但是，哪些基因易于这些 肿瘤，因此将是基于精确中等医学素的预防和治疗方法的靶标 主要是未知的。适当的最近确定了第一个孟德尔基因，易于tgct，也确定了 TGCT的新基因组关联击中。在这里提出的研究项目中，我们将确定 这些基因组变异损害细胞自主生殖细胞规范和/或的机制 表观遗传重编程（AIM 1）和性腺小裂形成（AIM 2）。我假设等位基因 倾向于TGCT损害生殖细胞发育的特定阶段。这些目标将使用 具有诱导多能干细胞（IPSC）的人类生殖细胞的创新建模和遗传生物库 约有100,000名具有表型数据的儿童，可以通过这些数据来识别患有性腺/生殖器的患者 TGCT。这些数据将提高我们对TGCT倾向和主动性的理解，并将扩大我们的 了解典型的性腺发育。这项研究的结果将为将来的精度提供理由 预防癌症和治疗策略。该提案描述了申请人的五年计划 作为一名专注于生殖细胞肿瘤的学术肿瘤学家发展独立的研究职业 倾向和预防。申请人Pyle博士是儿童医院的儿科遗传学家 费城（CHOP）的基本分子生物学和精确医学的博士学位培训。她的研究 专注于识别易感TGCT的种系遗传特征，并了解其 作用机理。该奖项的目标是进一步发展成功职业所需的技能 作为独立研究者，包括生物信息学分析和处理大遗传和处理的专业知识 表型数据集，使用IPSC的人体组织建模以及癌症生物学。该奖项的导师， 博士。 Hakon Hakonarson和Katherine L. Nathanson是儿科的国际公认领导人 遗传发现和遗传易感性癌症。 Pyle博士将得到 属于肿瘤学，统计遗传学和性腺发展领域的领导者。 Pyle博士 还将受益于CHOP和University of University的无与伦比的资源和精通资源 宾夕法尼亚州。

项目成果

Clinical Effectiveness of Telemedicine-Based Pediatric Genetics Care.

• DOI: 10.1542/peds.2021-054520
• 发表时间: 2022-07-01
• 期刊: PEDIATRICS
• 影响因子: 8
• 作者: Szigety, Katherine M.;Crowley, Terrence B.;Gaiser, Kimberly B.;Chen, Erin Y.;Priestley, Jessica R. C.;Williams, Lydia S.;Rangu, Sneha A.;Wright, Christina M.;Adusumalli, Priyanka;Ahrens-Nicklas, Rebecca C.;Calderon, Brandon;Cuddapah, Sanmati R.;Edmondson, Andrew;Ficicioglu, Can;Ganetzky, Rebecca;Kalish, Jennifer M.;Krantz, Ian D.;McDonald-McGinn, Donna M.;Medne, Livija;Muraresku, Colleen;Pyle, Louise C.;Zackai, Elaine H.;Campbell, Ian M.;Sheppard, Sarah E.
• 通讯作者: Sheppard, Sarah E.

Behavioral Health Diagnoses in Youth with Differences of Sex Development or Congenital Adrenal Hyperplasia Compared with Controls: A PEDSnet Study.

• DOI: 10.1016/j.jpeds.2021.08.066
• 发表时间: 2021-12
• 期刊: The Journal of pediatrics
• 作者: Sewell R;Buchanan CL;Davis S;Christakis DA;Dempsey A;Furniss A;Kazak AE;Kerlek AJ;Magnusen B;Pajor NM;Pyle L;Pyle LC;Razzaghi H;Schwartz BI;Vogiatzi MG;Nokoff NJ
• 通讯作者: Nokoff NJ