# Heme allocation and disruptions in asthma and the failing heart

> **NIH NIH K99** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $99,661

## Abstract

PROJECT SUMMARY/ABSTRACT
Title: Heme allocation and disruptions in asthma and the failing heart
The candidate, Dr. Sweeny, is a postdoctoral fellow dedicated to developing a successful independent
research career investigating heme homeostasis and allocation in healthy and disease states with a specific
focus on key proteins and small molecule stimuli. With a strong background in biochemistry, biophysics, and
molecular biology, the candidate has developed new expertise in cell biology techniques and will use the
mentored phase of this award to move into translational research. The Career Development Plan outlined in
this proposal covers two years of mentored training including technical skill training, career development
activities, and guidance by an excellent advisory committee to facilitate the successful transition to
independence. Research Plan: Heme proteins play a role in a number of crucial cellular processes, however,
free heme is highly toxic and therefore its production, degradation and delivery must be tightly regulated. Heme
delivery and insertion into heme proteins is essential for their function, and reallocation of heme in response to
stimuli is crucial to maintain normal cellular activity, nevertheless, details of the heme homeostasis system and
directed delivery upon stimuli remain elusive. The overarching goal of this research is to understand how heme
homeostasis and heme allocation are controlled and regulated in cells, and to determine disruptions to these
pathways in disease. Recent findings have identified three major players in heme sequestration, delivery and
insertion into downstream proteins; GAPDH, nitric oxide (NO) and Hsp90. In Aim 1, during the mentored phase
of the award, Dr. Sweeny will elucidate how NO and Hsp90 stimulate insertion of GAPDH-bound heme into the
downstream heme proteins soluble guanylyl cyclase (sGC) and NADPH oxidase 5 (NOX5). Both sGC and
NOX5 are implicated in a number of human diseases including asthma and cardiovascular disorders. This aim
will be primarily carried out in model mammalian cell systems, supported by in vitro biochemical and
biophysical assays, by investigating the interplay of Hsp90 and GAPDH, the effect of NO on GAPDH heme
related activities, and determining the role of STIP1/HOP in the heme transfer machinery. In Aim 2, Dr.
Sweeny will study the regulation of these downstream heme proteins in the context of human disease; asthma
(sGC) and atrial fibrillation (AF) (NOX5). Aim 2A experiments will be carried out using airway smooth muscle
cells from patients with severe asthma and age/gender/race matched controls. Aim 2B focuses on studying
NOX5 regulation and contribution to disease in AF. This work will be carried out using tissue from AF patients
undergoing cardiac surgery, and from donor hearts in sinus rhythm, and using cardiomyocytes differentiated
from patient derived induced pluripotent stem cells. Aim 2B, translational research in heme homeostasis and
allocation in the ...

## Key facts

- **NIH application ID:** 9985620
- **Project number:** 5K99HL144921-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Elizabeth A. Sweeny
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $99,661
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985620

## Citation

> US National Institutes of Health, RePORTER application 9985620, Heme allocation and disruptions in asthma and the failing heart (5K99HL144921-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9985620. Licensed CC0.

---

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