# Kinase Dysfunction in Autism and Neurodevelopmental Disorders

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $732,678

## Abstract

ABSTRACT
 Kinase signaling exquisitely orchestrates each step of neuronal development, beginning at neurogenesis
to neuronal integration into functional synaptic networks. Through their highly specific substrate phosphorylation,
protein kinases regulate neuronal growth, activity and their plasticity. Despite the increasing evidence for a critical
and causative role of kinase dysfunction in neurodevelopmental disorders (NDD), the mechanisms through which
the human kinome controls neuronal development and how its dysfunction manifests in disease remain major
gaps in the field of neurodevelopmental biology. In this proposal, we will investigate the role of protein kinase
TAOK1, genetic mutations in which have been strongly associated with autism spectrum disorder, macrocephaly
and neurodevelopmental delay. Based on our preliminary findings, the central hypothesis of this research
proposal is that TAOK1 is a pleiotropic kinase that regulates neuronal development through its ability to directly
bind phospholipids and remodel the neuronal membrane, and that dysfunction in TAOK1 signaling lead to
neuropathogenesis. Our data show that (a) both de novo and inherited TAOK1 mutations in NDD induce aberrant
neuronal membrane extensions that disrupt neuronal morphology and function and (b) TAOK1 can directly bind
phosphoinositides enriched in the plasma membrane. Through integration of innovative approaches in
proteomics, chemical-genetics, structural biology, stem cell technology and human disease relevant model
systems, we seek to (Aim1) understand the mechanisms through which TAOK1 signaling mediates neuronal
development, (Aim2) determine the biological principles that govern TAOK1 membrane binding and remodeling,
and (Aim3) generate human stem cell derived neuronal models of TAOK1 associated disease in order to
determine developmental perturbations as well as phosphoproteomic changes due to deficits in TAOK1
signaling. These studies will provide a comprehensive understanding of the role of a high confidence gene in the
etiology of neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 10809666
- **Project number:** 5R01MH130336-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Smita Yadav
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $732,678
- **Award type:** 5
- **Project period:** 2023-03-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809666

## Citation

> US National Institutes of Health, RePORTER application 10809666, Kinase Dysfunction in Autism and Neurodevelopmental Disorders (5R01MH130336-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10809666. Licensed CC0.

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