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: 10439873
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439873
• 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 Hamartoma Tumor Syndrome; PTEN autism spectrum disorder; PTEN gene; 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互动组：结构和功能动态网络体系结构的建模 癌症和自闭症的治疗调节 候选人艾里斯·尼拉·史密斯博士是一名博士后研究员，致力于培养一名成功的独立人士 作为两个新兴领域--计算生物物理学和基因组学--信息医学的桥梁的研究生涯。 她将在研究生殖系的基因组学信息医学实验技术方面开发新的专业知识。 PTEN基因突变易患罕见遗传性癌症PTEN错构瘤肿瘤综合征 易感综合症，有趣的是，自闭症谱系障碍(ASD)的最常见原因之一。 她将在发展成为独立调查员所需的计算技能的基础上再接再厉 在那里，她将询问与子宫内膜异位症的易感性和临床严重性相关的PTEN结构，以及 对异质性疾病研究不足，建立更精细的疾病分类方案 分层、诊断和治疗。职业发展计划列出了两年的指导培训 包括技术技能培训，职业发展活动，以及优秀导师、合作导师的指导， 和咨询委员会，以促进向独立的成功过渡。研究计划：PTEN 调节失调常见于癌症和包括ASD在内的神经发育障碍。另外， 患有PHTS的妇女会患上子宫内膜异位症，这是子宫内膜癌的高风险因素。然而，一个完整的 了解导致PTEN功能失调的改变的影响，特别是当 与PTEN突变相关的基因仍然难以捉摸。这项研究的首要目标是勾勒出 PTEN调节失调的机制进一步有助于识别有器官特异性癌症风险的患者 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 在PTEN相关的病理过程中，PPI可以动态改变PTEN的活性和随后的功能影响。在……里面 特异性AIMS(SA)1和2(K99)，史密斯博士将广泛表征与PTEN相关的生殖系突变 与癌症和/或ASD的结果有关。在SA1A中，她将阐明不同的疾病特异性相互作用和 来自PHTS癌症和/或患者的永生化淋巴母细胞系的结构拓扑 ASD与年龄/性别/种族相匹配的对照组。SA1B专注于了解不同的蛋白质拓扑结构和 癌症与ASD中蛋白质间和蛋白质内的相互作用。这项工作将在人类乳腺癌上进行。 (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)患者来源的诱导多能干细胞体外交联质谱质谱衍生 全长PTEN的从头结构。在SA2中，史密斯博士将利用电子计算机建模来询问构象 动力学和PTEN C-Tail PPI作为癌症和ASD相关PTEN突变的潜在治疗靶点。 SA3在子宫内膜异位症的电子分子模拟研究中，超出了导师的实验室的范围，并 将在R00阶段进行。这一应用程序建立在强大的初步数据、支持性研究 环境，以及由公认和成功的科学领袖组成的咨询委员会。

项目成果

The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane.

• DOI: 10.1016/j.isci.2021.102438
• 发表时间: 2021-05-21
• 期刊: iScience
• 影响因子: 5.8
• 作者: Jang H;Smith IN;Eng C;Nussinov R
• 通讯作者: Nussinov R