# Animal Models for Studying the Genetics of Complex Diseases

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $770,952

## Abstract

Aging-associated common human diseases such as hypertension and diabetes mellitus are influenced by
small changes in multiple genetic factors, but the precise nature of each factor is still unclear. Our long-term
goal is to gain deeper understanding of genetic risk factors for the common diseases by developing mouse
models that closely mimic human genetic variations. ELMO1 locus, encoding engulfment and cell motility
protein 1, is associated with diabetic nephropathy in humans. With a novel mouse model system, we
established that the graded increase in the levels of ELMO1 determines the severity of nephropathy and
cardiomyopathy in diabetic mice through increased production of reactive oxygen species (ROS). We further
found that a high-dose vitamin B12, a natural superoxide scavenger, prevents and even restores the cardiac
dysfunction in diabetic mice. ELMO-DOCK (dedicator of cytokinesis) complex is a guanine nucleotide
exchange factor (GEF) that activates RAC (Ras-related C3 botulinum toxin substrate). Activated RAC not only
triggers actin remodeling, cell growth and motility, but also is essential for the activation of NADPH oxidases, a
major producer of ROS. However, why ELMO1 is so critical in diabetic complications of parenchymal cells
remains unknown. Excess ROS is a common factor in aging-associated diseases, and acute tissue injuries
that follow ischemia reperfusion (IR) and infection. IR induced acute kidney injury (AKI) is also preventable
with B12, and our preliminary data suggest that ELMO1 is involved in determining the severity of AKI. ELMO-
DOCK-RAC is evolutionally conserved as an initiator of clearing process of apoptotic cell corpse and organelle,
which is in part an attempt to salvage basic elements such as nucleotides and amino acids during cell damage
and apoptosis/death. Salvaging is good when these elements are scarce, but in abundance, excess ROS
production only does harm. Accordingly, we propose a hypothesis that ELMO1 activates RAC in parenchymal
cells responding to cellular stress and damage, and inadvertently influences the severities of
disease/conditions. We will test this hypothesis with three Specific Aims; (1) to examine the effects
hyperglycemia, hyperlipidemia and other factors altered by diabetes have on neonatal cardiomyocytes in
culture, and the roles of ELMO1-dependent RAC1 activation in angiotensin II induced cardiac hypertrophy and
failure in vivo; (2) to investigate ELMO1-dependent RAC1 activation in ischemic AKI, and its related cardiac
complications, and explore the possible involvement of ELMO1 in acute respiratory distress syndrome (ARDS),
the severity which is greatly enhanced by age and comorbidities in the current COVID pandemic; and (3) to
determine the beneficial effects beyond superoxide scavenging which vitamin B12 execute on diabetic
cardiomyopathy. Ultimately, increased understanding of factors influencing the severity of aging-associated
common diseases should help lead us to a deeper knowle...

## Key facts

- **NIH application ID:** 10365229
- **Project number:** 2R01HL049277-30A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** NOBUYO MAEDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $770,952
- **Award type:** 2
- **Project period:** 1992-09-30 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365229

## Citation

> US National Institutes of Health, RePORTER application 10365229, Animal Models for Studying the Genetics of Complex Diseases (2R01HL049277-30A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10365229. Licensed CC0.

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