# Pathogenesis of Dyslipidemia and Atherosclerosis in the Diabetic State

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $442,500

## Abstract

Abstract:
The leading cause of death in diabetic patients is cardiovascular disease (CVD). Our
long-term goal is to identify new therapeutic targets for the prevention of CVD in diabetic
patients. In the last grant cycle, we identified the enzyme, flavin-containing
monooxygenase 3 (FMO3) as a potential mediator of diabetes associated cardiovascular
disease. FMO3 is suppressed by insulin and increased in the livers of obese/diabetic
subjects; moreover, knockdown of FMO3 completely prevented the development of
hyperglycemia, hyperlipidemia and atherosclerosis in insulin resistant mice. The FMO3
pathway is exciting because of the striking magnitude of the effects observed in insulin
resistant mice and the fact that early studies suggest that FMO3 is also dysregulated in
diabetic humans. Moreover, the fact that FMO3 was identified via non-biased
approaches suggests that it may be a central pathway discovered only now that the
proper tools have become available. The overall goal of this proposal is to define the
mechanistic links in the diabetes/FMO3/atherosclerosis pathway, focusing on the
transcription factor, Sterol Regulatory Element Binding Protein (SREBP)-2, which we
have identified as a mediator of FMO3's actions. Our aims are as follows: (1)
determine how insulin and diabetes regulate FMO3; (2) define the product or target of
the FMO3 enzyme required for its downstream effects; and (3) define the mechanism by
which FMO3 alters cholesterol metabolism to induce SREBP-2. We expect that these
studies will provide the mechanistic detail necessary to determine if and how the FMO3
pathway can be manipulated for therapeutic use.

## Key facts

- **NIH application ID:** 9927682
- **Project number:** 5R01HL109650-10
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Sudha B Biddinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,500
- **Award type:** 5
- **Project period:** 2011-09-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927682

## Citation

> US National Institutes of Health, RePORTER application 9927682, Pathogenesis of Dyslipidemia and Atherosclerosis in the Diabetic State (5R01HL109650-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9927682. Licensed CC0.

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