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.

项目摘要/摘要 解开PTEN Interactome：建模结构和功能动态网络体系结构 用于癌症和自闭症的治疗调节 候选人Iris Nira Smith博士是致力于建立成功独立的博士后研究员 桥接两个新兴领域的研究职业 - 计算生物物理学和基因组知识医学。 她将在基因组知识医学研究生殖线领域的实验技术方面发展新的专业知识 PTEN突变，易于PTEN Hamartoma肿瘤综合征（PHTS），这是一种罕见的遗传癌 倾向综合征，以及自闭症谱系障碍最常见的原因之一（ASD）。 她将建立发展为独立调查员所需的计算技能的武器库 她将在其中询问与子宫内膜异位症的倾向和临床严重程度有关的PTEN结构 研究不足的异质疾病，以建立更精致的分类方案以改善疾病 分层，诊断和治疗。职业发展计划概述了两年的指导培训 包括技术技能培训，职业发展活动以及出色的心理，同事的指导， 和促进成功过渡到独立性的咨询委员会。研究计划：PTEN 在包括ASD在内的癌症和神经发育障碍中经常观察到失调。此外， 患有PHT的妇女出现子宫内膜癌风险高的子宫内膜异位症。但是，一个完整 了解导致PTEN功能失调的改变的影响，尤其是在 与PTEN突变相关，仍然难以捉摸。这项研究的总体目标是描述 PTEN失调的机制，以进一步帮助鉴定有器官特异性癌症患者的能力 和自闭症。最近的发现表明，翻译后修饰和关键的蛋白质蛋白质相互作用 （PPI）可以动态地改变PTEN活性，并在与PTEN相关的病理学中的随后功能影响。 具体目的（SA）1和2（K99），史密斯博士将广泛地表征与生殖线突变相关的生殖线突变 与癌症和/或ASD结局。在SA1A中，她将阐明不同的特异性相互作用体和 永生的淋巴细胞细胞系中的结构拓扑结构，这些细胞系来自PHTS患者和/或 ASD和年龄/性别/种族匹配的控件。 SA1B专注于了解各种蛋白质拓扑和 癌症与ASD的蛋白质间相互作用和蛋白质内相互作用。这项工作将在人类乳腺癌中进行 （BT549）和非恶性乳腺（MCF10A）和甲状腺（NTHY-ORI 3-1）细胞，以及神经元分化 （ASD）使用体外交联的质谱法衍生的患者衍生的诱导多能干细胞 全长PTEN的从头结构。在SA2中，史密斯博士将在硅造型中使用构象 动力学和PTEN C-tail PPI作为癌症和ASD相关PTEN突变的潜在治疗靶标。 SA3在子宫内膜异位症中的硅分子建模研究中，超出了精神实验室的范围 将在R00阶段进行。该应用程序建立在强大的初步数据的基础上，这是一项支持的研究 环境和咨询委员会与公认和成功的科学领袖。