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

> **NIH NIH K99** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $100,000

## Abstract

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 conformati...

## Key facts

- **NIH application ID:** 10282792
- **Project number:** 1K99GM143552-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Iris Nira Smith
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $100,000
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10282792

## Citation

> US National Institutes of Health, RePORTER application 10282792, Unraveling the PTEN Interactome: Modeling Structural and Functional Dynamic Network Architecture for Therapeutic Modulation in Cancer and Autism (1K99GM143552-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10282792. Licensed CC0.

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