Unraveling the PTEN Interactome: Modeling Structural and Functional Dynamic Network Architecture for Therapeutic Modulation in Cancer and Autism

揭开 PTEN 相互作用组：为癌症和自闭症治疗调节的结构和功能动态网络架构建模

• 批准号: 10282792
• 负责人: Iris Nira Smith
• 金额: $ 10万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 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/10282792
• 关键词: 3-Dimensional; Active Sites; Address; Advisory Committees; Affect; Binding; Biophysics; Breast; C-terminal; Catalysis; Cell Differentiation process; Cells; Classification Scheme; Clinical; Communication; Complex; Data; Development Plans; Diagnosis; Disease; Disease stratification; Drug Targeting; Endometrial; Endometrial Carcinoma; Environment; Functional disorder; Gender; Genes; Genomics; Goals; Human; Immunoprecipitation; In Vitro; Individual; Inherited; Iris; Knowledge; Lead; Length; MCF10A cells; Macrocephaly; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Medicine; Mentors; Modeling; Molecular Conformation; Mutate; Mutation; Neurodevelopmental Disorder; Neuronal Differentiation; Non-Malignant; Organ; Outcome; PTEN gene; PTEN protein; Pathology; Pathway interactions; Patients; Phase; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Play; Population; Post-Translational Protein Processing; Postdoctoral Fellow; Predisposition; Protein Conformation; Proteins; Race; Regulation; Research; Research Personnel; Risk; Role; Severities; Signal Transduction; Site; Structural Models; Structure; Syndrome; Tail; Technical Expertise; Techniques; Therapeutic; Thermodynamics; Thyroid Gland; Training; Tumor Suppressor Genes; Tumor Suppressor Proteins; Variant; Woman; Work; autism spectrum disorder; autistic children; base; cancer predisposition; cancer risk; career; career development; crosslink; early onset; endometriosis; fighting; high risk; improved; in silico; induced pluripotent stem cell; insight; interdisciplinary approach; lifetime risk; lymphoblastoid cell line; malignant breast neoplasm; molecular modeling; network architecture; network models; neurodevelopment; novel; protein protein interaction; skills; skills training; targeted treatment; therapeutic development; therapeutic target

PROJECT SUMMARY/ABSTRACT Unraveling the PTEN Interactome: Modeling Structural and Functional Dynamic Network Architecture for Therapeutic Modulation in Cancer and Autism The candidate, Dr. Iris Nira Smith, is a postdoctoral fellow dedicated to developing a successful independent research career that bridges two burgeoning fields – computational biophysics and genomics-informed medicine. She will develop new expertise in experimental techniques in genomics-informed medicine studying germline PTEN mutations which predispose to PTEN hamartoma tumor syndrome (PHTS), a rare inherited cancer predisposition syndrome, and intriguingly one of the most common causes of autism spectrum disorder (ASD). She will build on the armamentarium of computational skills needed to develop into an independent investigator where she will interrogate PTEN structure relevant to predisposition and clinical severity of endometriosis, an under-studied heterogeneous disease, to establish a more refined classification scheme for improved disease stratification, diagnosis, and treatment. The Career Development Plan outlines two years of mentored training including technical skill training, career development activities, and guidance by an excellent mentor, co-mentor, and advisory committee to facilitate the successful transition to independence. Research Plan: PTEN dysregulation is frequently observed in cancer and neurodevelopmental disorders including ASD. Additionally, women with PHTS develop endometriosis which has a high risk for endometrial cancer. However, a full understanding of the effects of alterations that contribute to dysregulated PTEN function, particularly when associated with PTEN mutations, remains elusive. The overarching goal of this research is to delineate the mechanism of PTEN dysregulation to further aid in the ability to identify patients at risk for organ-specific cancers and autism. Recent findings reveal that post-translational modifications and crucial protein-protein interactions (PPIs) can dynamically change PTEN activity and subsequent functional impact in PTEN-related pathologies. In Specific Aims (SA) 1 and 2 (K99), Dr. Smith will extensively characterize germline PTEN mutations associated with cancer and/or ASD outcomes. In SA1A, she will elucidate distinct disease-specific interactomes and structural topologies in immortalized lymphoblastoid cell lines derived from PHTS individuals with cancer and/or ASD and age/gender/race matched controls. SA1B focuses on understanding diverse protein topologies and inter- and intra-protein interactions in cancer versus ASD. This work will be carried in human breast cancer (BT549) and non-malignant breast (MCF10A) and thyroid (Nthy-ori 3-1) cells, as well as neuronally differentiated (ASD) patient-derived induced pluripotent stem cells using in vitro cross-linking mass spectrometry MS to derive de novo structure of full-length PTEN. In SA2, Dr. Smith will utilize in silico modeling to interrogate conformational dynamics and PTEN C-tail PPIs as potential therapeutic targets in cancer- and ASD-associated PTEN mutations. SA3, in silico molecular modeling research in endometriosis, extends beyond the scope of the mentor’s lab and will be carried out in the R00 phase. This application builds upon strong preliminary data, a supportive research environment, and advisory committee with recognized and successful scientific leaders.

项目总结/文摘