# The Role of Pten in Congenital Hydrocephalus

> **NIH NIH F31** · YALE UNIVERSITY · 2022 · $31,607

## Abstract

PROJECT SUMMARY/ ABSTRACT
Congenital hydrocephalus (CH), featuring enlarged brain ventricles, has been classically attributed to failed
cerebrospinal fluid (CSF) homeostasis and treated with surgical CSF shunting with high morbidity and failure
rates. Significant gaps in our understanding of the molecular mechanisms of human CH impede development
of preventive measures and targeted therapies. Using whole exome sequencing (WES), we recently
demonstrated de novo mutations (DNMs) in four different neural stem cell (NSC) regulators cause >10% of
sporadic human CH (Neuron, 2018). All four genes regulate NSC fate, implicating dysregulated neural stem
cell development rather than primary CSF over-accumulation in a subset of CH patients, with potentially
paradigm-changing ramifications. In subsequent WES studies >200 CH patients, we have identified the PTEN-
PI3K-mTOR signaling pathway as the most commonly mutated gene module in sporadic human CH to date,
with multiple loss-of-function (LoF) DNMs in PTEN. Nonetheless, the physiological, cellular, and developmental
mechanisms by which PTEN LoF causes CH is unknown. Corroborating our human genetic findings, we now
find that embryonic conditional deletion of Pten in a discrete subset of NSCs is sufficient to cause lethal,
postnatal CH in mice. Aim 1 of this study will use detailed histological examination and advanced imaging to
characterize the ventricular morphology and cerebrospinal spinal fluid dynamics of hydrocephalic Pten cKO
mice. Successful completion of this Aim will help further our understanding of the pathophysiology of human
PTEN-associated CH. Aim 2 of this study will use immunofluorescent confocal microscopy imaging and
immunoblot analysis of the ventricular epithelium to examine neural stem cell differentiation and development
into mature ependymal cells and mTor pathway activation, underlying the development of hydrocephalus in
Pten cKO mice. Based on promising preliminary data, we will also use delivery of rapamycin, an FDA-
approved mTOR inhibitor, to attenuate the progression of CH in Pten cKO mice. Successful completion of this
Aim will provide insight into the cellular and molecular mechanisms of PTEN-mutated human CH, setting the
stage for near-term pre-clinical and translational studies. In addition, this application details research
mentorship, clinical experiences, advanced coursework, training of new techniques, and development of the
needed skills in scientific grantsmanship, writing, and presentation. This F31 fellowship will serve as an
important training tool in the applicant’s development of a patient-driven research program as an independent
investigator and neurosurgeon.

## Key facts

- **NIH application ID:** 10332522
- **Project number:** 5F31NS115519-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Tyrone DeSpenza
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $31,607
- **Award type:** 5
- **Project period:** 2020-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10332522

## Citation

> US National Institutes of Health, RePORTER application 10332522, The Role of Pten in Congenital Hydrocephalus (5F31NS115519-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10332522. Licensed CC0.

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