# An integrated approach to the study of mitochondrial vitamin B12 pathway and type II fatty acid synthesis

> **NIH NIH R00** · YALE UNIVERSITY · 2021 · $249,000

## Abstract

Abstract
The dysregulation of the metabolic pathways is the direct cause of inborn errors of metabolism and also
leads to common diseases like cancers and diabetes. The applicant's long-term objective is to develop
an integrated strategy combining computation, CRISPR genome editing and metabolomics to study the
poorly characterized metabolic pathways underlying human diseases. The results of these studies will
generate novel hypotheses for diagnosing metabolic diseases of unknown causes and provide
alternative directions for disease interventions. The applicant has previously obtained rigorous graduate
training in biochemistry and cell biology, including membrane lipid biology. During the ongoing NRSA
F32 postdoctoral funding period, the applicant has developed an integrated approach to study a
mitochondrial enzyme of unknown function, CLYBL, and revealed its function in regulating mitochondrial
vitamin B12 (B12)-dependent processes. This finding mirrors previous human genetic studies that
associate loss-of-function of CLYBL with low circulating B12 levels. For the K99/R00 application, the
applicant proposes to focus on two mitochondria-localized, essential metabolic pathways in human: (1) to
identify missing regulators of the mitochondrial B12 pathway; (2) to perform loss-of-function studies of
the mitochondrial type II fatty acid synthesis (mtFASII). To achieve these goals, two major strategies will
be applied: (a) to leverage genome-wide computational approaches and publicly available databases to
predict new pathway regulators; (b) to combine CRISPR editing in cultured cells and high-resolution LC-
MS based metabolomics (including lipidomics) and proteomics (including top-down proteomics) to probe
metabolism. The applicant's host laboratory and institute provide an ideal training environment for the
proposed research. Her postdoctoral mentor Dr. Vamsi Mootha's laboratory has previously developed
genome-wide computational methods to predict the mitochondrial proteome – the same toolset that
could predict novel metabolic regulators. The laboratory is also an early adopter of metabolomics and
part of the Broad Institute Metabolism Program. The applicant has obtained initial training in LC-MS
methods to profile polar metabolites. And during the K99/R00 funding period, she will receive additional
training in lipidomics and advanced native proteomics method to study the fatty acid acyl-chain extension
during the mtFASII. Successful completion of this project will provide fundamental insights into
mitochondrial cofactor metabolism and regulation of lipid homeostasis, and might introduce new
directions for diagnosing metabolic diseases. Meanwhile, the career development plan will prepare the
applicant to transition into an independent investigator in the field of metabolism.

## Key facts

- **NIH application ID:** 10115068
- **Project number:** 5R00GM124296-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Hongying Shen
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115068

## Citation

> US National Institutes of Health, RePORTER application 10115068, An integrated approach to the study of mitochondrial vitamin B12 pathway and type II fatty acid synthesis (5R00GM124296-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115068. Licensed CC0.

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