# Nuclear lamins and the hepatocyte nuclear envelope in nonalcoholic fatty liver disease

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $168,900

## Abstract

Project Summary/Abstract
 This revised K08 proposal will complete Graham Brady, MD, PhD's training toward his goal of improving
our understanding and treatment of nonalcoholic fatty liver disease (NAFLD). Dr. Brady is a physician and
scientist in hepatology at the University of Michigan with clinical expertise in liver disease, graduate training in
cell biology and biochemistry, and established success in the field of NAFLD. This proposal builds on Dr.
Brady's prior experience, with new training in genomics, bioinformatics, and a unique model organism
(zebrafish). His existing expertise and newly-acquired skills will be integrated to advance our understanding of
the scope and mechanisms of nuclear lamina-related NAFLD. The research will be conducted under the
guidance of primary mentor Bishr Omary, MD, PhD, and co-mentors Liz Speliotes, MD, PhD, MPH, and Jordan
Shavit, MD, PhD, with Jun Li, PhD, as a collaborator, who have expertise in NAFLD, genomics, zebrafish, and
extensive mentoring success. The 5-year career development plan includes formal coursework, professional
development, and mentored research, with defined milestones to ensure productivity and a successful
transition to independence.
 The estimated global prevalence of NAFLD is now ~25%, but medical therapies are limited in number and
efficacy, partly due to incomplete understanding of its pathogenesis. A unique group of patients with mutations
in genes encoding nuclear lamina components develop early-onset NAFLD that often progresses to
steatohepatitis (NASH) with cirrhosis. Mechanisms of NAFLD/NASH due to nuclear lamina mutations are
obscure, but their study may provide insights into NAFLD pathogenesis and avenues for future therapies. This
proposal will test the hypothesis that genetic alteration of the nuclear lamina predisposes to NAFLD/NASH by
altering nuclear protein organization and the transcriptome. The mentored research has two Specific Aims:
  AIM 1: Identify and validate variants in nuclear lamina-related genes in NAFLD/NASH cohorts.
  AIM 2: Establish new experimental models to study how LMNA variants alter the nuclear lamina,
 heterochromatin, and transcriptome to promote NAFLD/NASH.
 In completing these aims, Dr. Brady will analyze genomic data linked to electronic medical record data in
unique NAFLD cohorts and develop new disease models that will provide mechanistic insights into lamina-
related NAFLD and in vivo systems for drug screening. This will build to two R01 proposals: (1) to examine the
mechanistic basis of NAFLD-associated variants identified in AIM 1 and (2) to examine the mechanisms and
therapeutic potential of screened compounds in the models generated in AIM 2. In addition to building a
foundation for a programmatic line of research to understand the role of the nuclear envelope in liver disease,
this K08 will provide Dr. Brady with research skills applicable to additional domains of hepatology and
genomics and equip him to establish himself as an in...

## Key facts

- **NIH application ID:** 9892203
- **Project number:** 1K08DK120948-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Graham F. Brady
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,900
- **Award type:** 1
- **Project period:** 2020-03-03 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892203

## Citation

> US National Institutes of Health, RePORTER application 9892203, Nuclear lamins and the hepatocyte nuclear envelope in nonalcoholic fatty liver disease (1K08DK120948-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9892203. Licensed CC0.

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