# Mechanisms and therapies for cerebellar development under defective mitochondrial metabolism

> **NIH NIH K08** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $195,288

## Abstract

Project Summary
This proposal describes a five-year career development program in the neurobiology of inborn errors of
mitochondrial metabolism. The principal investigator (PI) has completed postgraduate training in neurochemistry
and residency training in pediatric neurology at UT Southwestern. He has a strong background in the study of
neurometabolism and, over the course of this K08 award at The Rockefeller University, he aims to expand his
skills in advanced microscopy, transcriptomics, and metabolomics to study how defective mitochondrial
metabolism compromises brain development and causes disease. Mitochondrial disorders represent the most
common form of inborn errors of metabolism (1:3000 births). These disorders frequently disrupt the development
of the brain, particularly of the cerebellum, which is affected in ~70% of patients. The cerebellar phenotype is
especially pronounced in pyruvate dehydrogenase deficiency (PDHD), one of the most common mitochondrial
disorders in children, presenting clinically from severe cerebellar hypoplasia to intermittent ataxia. The lack of
mechanistic understanding of cerebellar deficits in mitochondrial diseases has prevented the expansion of
therapeutic options, which are currently limited to symptomatic treatments. The overall objective of this project
is to identify mechanisms that underlie cerebellar developmental disease in mitochondrial disorders and apply
effective therapies accordingly. To achieve this goal, the PI will investigate developmental and metabolic
mechanisms involved in abnormal cerebellar formation in the prototypical mitochondrial disease with cerebellar
involvement: PDHD. The PI will be mentored via customized tutorial interactions with his primary advisor, Dr.
Mary E. Hatten (neurodevelopment), and three co-mentors, Dr. Nathaniel Heintz (molecular neurobiology), Dr.
Justin Cross (metabolomics), and Dr. Thomas Carroll (bioinformatics). Preliminary data from a mouse model of
PDHD reveal that glucose metabolism in the cerebellum is impaired and that proliferation and migration of
granule cells (GC) is compromised. The central hypothesis is that PDHD disrupts cerebellar formation by limiting
GC development as a result of impaired glucose metabolism. Two specific aims are proposed: 1) to elucidate
developmental processes that underlie abnormal cerebellar formation in PDHD; and 2) to identify metabolic
mechanisms relevant to the cerebellar disease in this condition. Under the first aim, key steps of GC development
will be studied using advanced microscopy. For the second aim, proven transcriptomics and metabolomics will
be applied to identify and treat metabolic defects in the PDHD cerebellum. The research proposed is significant
because it is expected to advance our understanding of how mitochondrial diseases disrupt cerebellar
development and translate promising findings to patients. This proposal is innovative because it combines
advanced methodologies from developmental neurobiology ...

## Key facts

- **NIH application ID:** 10231085
- **Project number:** 5K08NS110877-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Isaac Marin-Valencia
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $195,288
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231085

## Citation

> US National Institutes of Health, RePORTER application 10231085, Mechanisms and therapies for cerebellar development under defective mitochondrial metabolism (5K08NS110877-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10231085. Licensed CC0.

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