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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

基本信息

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
项目类别：
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

项目摘要

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/摘要揭示PTEN相互作用组：结构和功能动态网络架构建模癌症和自闭症的治疗调节候选人，博士虹膜尼拉史密斯，是一个博士后研究员，致力于发展一个成功的独立研究事业，桥梁两个新兴领域-计算生物物理学和基因组学知情医学。她将在基因组学知情医学的实验技术方面发展新的专业知识， PTEN突变易患PTEN错构瘤肿瘤综合征（PHTS），一种罕见的遗传性癌症易感综合症，有趣的是，它是自闭症谱系障碍（ASD）最常见的原因之一。她将学习成为一名独立调查员所需的计算技能在那里她将询问与子宫内膜异位症的易感性和临床严重程度相关的PTEN结构，研究不充分的异质性疾病，以建立一个更精细的分类方案，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，以及优秀导师，共同导师，和咨询委员会，以促进向独立的成功过渡。研究计划：PTEN 在癌症和包括ASD的神经发育障碍中经常观察到失调。此外，本发明还患有PHTS的妇女发展为子宫内膜异位症，其具有子宫内膜癌的高风险。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描绘 PTEN失调的机制，以进一步帮助识别具有器官特异性癌症风险的患者的能力和自闭症。最近的研究结果表明，翻译后修饰和关键的蛋白质-蛋白质相互作用， PPIs可以动态改变PTEN活性和随后在PTEN相关病理中的功能影响。在具体目标（SA）1和2（K99），史密斯博士将广泛表征生殖系PTEN突变相关与癌症和/或ASD的结果。在SA 1A中，她将阐明不同的疾病特异性相互作用，来源于患有癌症和/或癌症的PHTS个体的永生化淋巴母细胞样细胞系中的结构拓扑学 ASD和年龄/性别/种族匹配的对照。SA 1B专注于了解不同的蛋白质拓扑结构，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中进行（BT549）和非恶性乳腺（MCF 10A）和甲状腺（Nthy-ori 3-1）细胞，以及神经元分化的 (ASD)使用体外交联质谱MS衍生患者来源的诱导多能干细胞，全长PTEN的从头结构。在SA 2中，Smith博士将利用计算机模拟建模来询问构象动力学和PTEN C-尾PPI作为癌症和ASD相关PTEN突变的潜在治疗靶点。 SA 3，在子宫内膜异位症的计算机分子建模研究，超出了导师实验室的范围，将在R 00阶段进行。该应用程序建立在强有力的初步数据基础上，环境和咨询委员会与公认的和成功的科学领导人。