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

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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.