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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.

项目概要/摘要揭开 PTEN Interactome 的面纱：对结构和功能动态网络架构进行建模用于癌症和自闭症的治疗调节候选人 Iris Nira Smith 博士是一名博士后研究员，致力于开发成功的独立研究生涯连接了两个新兴领域——计算生物物理学和基因组学医学。她将在基因组学信息医学研究种系的实验技术方面发展新的专业知识 PTEN 突变易患 PTEN 错构瘤综合征 (PHTS)，这是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。她将建立在发展成为一名独立调查员所需的计算技能的基础上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，尚未充分研究的异质性疾病，为改善疾病建立更精细的分类方案分层、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、共同导师的指导，和咨询委员会，以促进成功过渡到独立。研究计划：PTEN 在癌症和神经发育障碍（包括自闭症谱系障碍）中经常观察到失调。此外，患有 PHTS 的女性会出现子宫内膜异位症，患子宫内膜癌的风险很高。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，仍然难以捉摸。这项研究的总体目标是描绘 PTEN 失调的机制进一步帮助识别有器官特异性癌症风险的患者和自闭症。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 活性以及随后对 PTEN 相关病理的功能影响。在具体目标 (SA) 1 和 2 (K99)，Smith 博士将广泛描述与种系 PTEN 突变相关的特征与癌症和/或自闭症谱系障碍（ASD）结果相关。在 SA1A 中，她将阐明不同的疾病特异性相互作用组和来自患有癌症和/或的 PHTS 个体的永生化类淋巴母细胞系的结构拓扑 ASD 和年龄/性别/种族匹配的对照。 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 SA2 中，Smith 博士将利用计算机模拟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。 SA3 是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R00阶段进行。该应用程序建立在强大的初步数据和支持性研究的基础上环境，以及由公认的成功科学领袖组成的咨询委员会。