# The Role of PPM1G in Apolipoprotein E Biology and Atherosclerotic Cardiovascular Disease

> **NIH NIH K08** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $167,400

## Abstract

PROJECT SUMMARY/ABSTRACT
 This proposal details a comprehensive five-year training program for mentored career development in
functional genomics applied to preventive cardiovascular medicine. The applicant seeks to use DNA-aptamer
based proteomics profiling data from human plasma and genomics data to identify novel pathways in
atherosclerotic pathogenesis that can then be studied using animal, cell and molecular biology techniques.
The candidate is completing his clinical fellowship in cardiovascular medicine and will join the faculty at Beth
Israel Deaconess Medical Center upon graduation. The outlined proposal builds on the candidate’s clinical
training and strong background in molecular and cellular research following his Ph.D. in pharmacology to
provide two new domains of expertise through a blend of laboratory work, didactic courses, workshops, and
scientific conferences: bioinformatics in functional genomics and the use of murine models of cardiovascular
disease. The candidate’s mentor is a recognized leader in multi-omics molecular profiling in population-based
studies and translating these findings back to cell- and animal-based model systems. The scientific advisory
committee has a distinguished mentoring record and vast expertise in human genomics, murine models of
atherosclerosis and metabolism, and gene editing.
 The proposed research extends preliminary studies that integrated proteomics and genomics data in
two large population-based studies to identify a novel association between the phosphatase PPM1G and
plasma levels of apolipoprotein E (ApoE). This association was experimentally validated in vitro by knocking
down PPM1G in a human hepatocyte model, which led to the significant and specific down-regulation of ApoE
transcription and ApoE protein levels. The applicant now proposes to test the hypothesis that PPM1G is a
novel regulator of ApoE biology and contributes to early atherosclerotic pathogenesis in vivo using mouse
models. In Aim 1, the applicant will test whether knockdown of PPM1G modulates ApoE expression in mice.
In Aim 2, the applicant will examine whether knockdown of PPM1G modulates atherosclerotic lesion formation
in murine models. In Aim 3, the applicant will expand his functional genomics studies to identify additional
novel pathways in atherosclerotic pathogenesis and test their functional effects in model systems.
 Despite tremendous progress in preventive cardiology, atherosclerotic cardiovascular disease remains
the leading cause of mortality worldwide. This residual disease burden likely reflects important, undiscovered
biological pathways that underlie atherogenesis and that are not yet effectively targeted by available therapies.
This proposal aims to use emerging functional genomics approaches to identify novel pathways in early
atherosclerotic disease. By highlighting novel pathways, this research may ultimately lead to new targets for
preventive atherosclerotic therapy.

## Key facts

- **NIH application ID:** 10308397
- **Project number:** 5K08HL145095-04
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Mark Daniel Benson
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $167,400
- **Award type:** 5
- **Project period:** 2018-12-11 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308397

## Citation

> US National Institutes of Health, RePORTER application 10308397, The Role of PPM1G in Apolipoprotein E Biology and Atherosclerotic Cardiovascular Disease (5K08HL145095-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10308397. Licensed CC0.

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