# Pathological Mechanisms of Human Cerebeller Malformations

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $668,757

## Abstract

PROJECT SUMMARY/ABSTRACT
Numerous cerebellar malformations have been described in humans. Most cause cognitive, in addition to
motor and sensory integration deficits. Surprisingly little is understood regarding the developmental basis of
these malformations, particularly since little human specific data is available for normal or abnormal fetal
cerebellar development. This proposal seeks to advance knowledge of human cerebellar development and
malformations using human fetal samples and mouse models. The human-specific data will directly test the
validity of our working mouse-derived hypotheses regarding the causes these disorders and strengthen the
foundation of normal developmental data which will inform our ongoing genetic analyses of human cerebellar
malformations. We will conduct the first in-depth analysis of normal human fetal cerebellar development from
4-23 Gestational Weeks, covering major developmental events. We will then examine the pathology of human
fetal Dandy-Walker malformation the most common human cerebellar malformation, affecting ~1/3000 live
births. Mouse models will be generated in conjunction with these experiments to assess the mechanisms of the
developmental pathology. Finally, we will generate the first transcriptome data for normal human fetal
cerebellar neurons. These cell-type specific data are critically missing from current publicly available brain
resources. Our human fetal cerebellar neuron data will be compared to transcriptome data from existing
datasets of endogenous mouse developing cerebellar neurons as well as mES and hPSC-derived cerebellar
neurons to development to assess their validity as model systems. Further, the data will also be integrated with
exome data from human cerebellar malformation patients to facilitate gene discovery for these important and
understudied birth defects.

## Key facts

- **NIH application ID:** 9970549
- **Project number:** 5R01NS095733-05
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Kathleen Joyce Millen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $668,757
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970549

## Citation

> US National Institutes of Health, RePORTER application 9970549, Pathological Mechanisms of Human Cerebeller Malformations (5R01NS095733-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9970549. Licensed CC0.

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