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.

项目概要 睾丸生殖细胞肿瘤 (TGCT) 是 15-45 岁男性和成人中最常见的癌症 癌症会导致生命中最长的寿命损失。患有性腺/生殖器异型性的儿童（申请人的 专业），性腺生殖细胞肿瘤的终生风险高达50%。然而，哪些基因容易导致这些 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 大多不为人知。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）。我假设等位基因 易受 TGCT 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 TGCT。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。 了解典型性腺发育。这项研究的结果将为未来的精度提供依据 癌症预防和治疗策略。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 倾向和预防。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博士学位培训。她的研究 专注于识别易受 TGCT 影响的种系遗传特征，并了解其特征 行动机制。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 表型数据集、利用 iPSC 进行人体组织建模以及癌症生物学。此次获奖的导师， 博士。 Hakon Hakonarson 和 Katherine L. Nathanson 是儿科领域国际公认的领导者 分别是遗传发现和癌症遗传易感性。派尔博士将得到以下人员的支持 由肿瘤学、统计遗传学和性腺发育领域的领导者组成的指导委员会。派尔博士 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。

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