# Cellular and molecular mechanisms of diabetic atherosclerosis

> **NIH NIH R00** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $249,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Cardiovascular disease (CVD) due to atherosclerosis represents the leading cause of death worldwide.
Progress in preventing CVD has been stalled by the growing epidemic of obesity, insulin resistance and type 2
diabetes (T2D), which increases the relative risk of developing atherosclerotic vascular disease and its
complications four-fold compared to non-diabetic individuals. Despite this, the cellular and molecular
mechanisms underlying the incidence of diabetic atherosclerosis are still unclear, as are appropriate strategies
for the prevention and treatment of CVD in diabetic patients. We have recently developed an orally available,
liver-directed controlled release mitochondrial protonophore (CRMP) that promotes oxidation of hepatic
triglycerides by promoting a subtle sustained increase in hepatic mitochondrial inefficiency and shown that this
agent safely reverses hypertriglyceridemia, fatty liver, insulin resistance and liver fibrosis in rodent and
nonhuman primate models of obesity. Here, we will leverage the insulin-sensitizing effects of CRMP to directly
assess the role of hyperinsulinemia and insulin resistance in driving diabetic atherosclerosis in a murine model
of metabolic syndrome (Aims 1 and 2). We hypothesize that chronic CRMP treatment will reduce hepatic
steatosis, insulin resistance and dyslipidemia due to increases in rates of hepatic mitochondrial fat oxidation,
which in turn will reduce susceptibility to atherosclerosis. In addition, we will develop and utilize novel state-of-
the-art metabolic tracer methods to characterize the regulation of macrophage immunometabolism during
diabetic atherosclerosis (Aim 3), as the relationship between the inflammatory status and bioenergetic profile of
plaque macrophages in vivo, as well as its impact on atherosclerotic development and stability, remains largely
unknown. We hypothesize that obesity and T2D will increase glucose availability and utilization in
macrophages which will initiate a feed forward loop that fosters inflammation and further aggravates
atherosclerosis Collectively, this work will provide meaningful insight into the mechanisms regulating diabetic
atherosclerosis and will be critical for understanding the therapeutic utility of liver-directed mitochondrial
uncoupling agents for the treatment of cardiometabolic diseases. Therefore, we propose a focused career
development training plan during which the applicant will be trained in the responsible conduct of research,
learning all aspects of atherosclerotic plaque sectioning and characterization; the development and utilization
of stable isotope methods to assess macrophage immunometabolism; and bioinformatics analysis of large data
sets. This will be carried out under the supervision of the candidate’s primary mentor Dr. Gerald Shulman, co-
mentor Dr. William Sessa, and collaborators Drs. Carlos Fernandez-Hernando and Rachel Perry. By
completing the proposed training outlined in this application...

## Key facts

- **NIH application ID:** 10556834
- **Project number:** 4R00HL150234-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Leigh Goedeke
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10556834

## Citation

> US National Institutes of Health, RePORTER application 10556834, Cellular and molecular mechanisms of diabetic atherosclerosis (4R00HL150234-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10556834. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*