Mark Gladwin
University of Maryland, Baltimore, MD·Medicine & Clinical Research
Red blood cells and related iron-containing proteins control how oxygen and small signaling gases move through the body, and small changes in that chemistry can decide whether an airway clears mucus, whether a poisoning victim recovers, or whether a blood transfusion works well. Work in this lab follows that theme across three projects: a little-understood heme protein called cytoglobin and its role in airway cilia and body patterning; engineered heme proteins designed to soak up carbon monoxide after poisoning; and the inherited genetic differences among blood donors that make stored red cells fragile or robust.
- Fields
Medicine & Clinical Research
Physiology
Biochemistry
- Topics
cytoglobin
neuroglobin
heme proteins
- Grants
- 3 known grants, through Jul 2028
What they work on
- Test whether airway epithelial cytoglobin, a heme protein of unknown function, forms a complex with cilia and nitric oxide synthase to tune nitric oxide signaling, using cytoglobin knockout, H81Q gain-of-function and K116E loss-of-function mice, zebrafish, and PCD patient airway cells.
- Determine whether drugs that activate the nitric oxide-soluble guanylate cyclase pathway restore ciliary beating and correct left-right patterning defects in zebrafish, mouse and human airway epithelial models of primary ciliary dyskinesia.
- Improve the engineered neuroglobin antidote Ngb-H64Q-CCC by adding modifications that raise its carbon monoxide binding affinity and protein stability for a safer toxicity profile in preclinical carbon monoxide poisoning models.
- Engineer RcoM, a bacterial carbon monoxide sensor protein, down to the smallest unit that still binds carbon monoxide with high affinity, and compare its stability and safety with the current lead scavenger in mice.
- Apply the lab's gas-binding chemistry to design new oxygen carrier molecules that could serve as blood substitutes.
- Define what red-cell gene variants found in a genome-wide study of 12,000 blood donors actually do, including the African American G6PD-deficiency variant and a SEC14L4 variant, using CRISPR-Cas9 humanized mouse colonies.
- Measure how donor genotype sets the limits of cold blood storage and post-transfusion survival in people, using FDA-approved high-sensitivity biotin labeling of autologous red blood cells.
More about the research
One project asks why patients with primary ciliary dyskinesia (PCD), an inherited disease in which the tiny hair-like cilia lining the airway fail to beat, have unusually low nitric oxide in their exhaled breath. Nitric oxide is a short-lived signaling gas made by enzymes called nitric oxide synthases. The lab reports that cytoglobin, a heme protein of previously unknown function, is needed for stage-specific nitric oxide signaling and ciliary motion in zebrafish and mice, including for setting up left-right body asymmetry. The proposal tests whether cytoglobin sits together with cilia and nitric oxide synthase as a working complex that tunes this signaling. Tools include cytoglobin knockout mice plus gain-of-function (H81Q) and loss-of-function (K116E) mutants that alter how the heme binds ligands and changes oxidation state, zebrafish models, and airway epithelial cells from PCD patients. A second aim tests drugs that activate the pathway downstream of nitric oxide, through the enzyme soluble guanylate cyclase, to see whether ciliary beating and developmental defects can be corrected.
Why it matters
Each project points toward a clinical change. Understanding how cytoglobin and nitric oxide control ciliary beating could reshape how ciliopathies such as PCD are diagnosed and treated, and may bear on mucus clearance in cystic fibrosis, smoking and viral infection. An infusible carbon monoxide scavenger could give paramedics a field antidote for a poisoning that kills and leaves survivors with cognitive damage. Mapping donor genetics may let blood banks set storage limits per donor and distinguish robust from fragile units.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Omics, mice and men: Development of precision transfusion medicine
NIH · Sep 2009 – Jul 2028
Airway epithelial cytoglobin regulates nitric oxide synthase and development of primary ciliary dyskinesia and situs inversus
NIH · Dec 2023 – Nov 2027
Antidote for inhaled CO poisoning based on mutationally engineered neuroglobin
NIH · Dec 2014 – May 2027
Closest labs
Ambika Bhagi
University of Minnesota, MN·Biochemistry
Use structure-guided protein design to reprogram how sensitive and selective the heme iron sensor enzymes DosS and DosT are to low oxygen, nitric oxide and carbon monoxide.
Kenneth Remy
Case Western Reserve University, OH·Medicine & Clinical Research
Measure how plasma proteins bind heme, the iron core of hemoglobin, during sepsis and after red blood cell transfusion compared with chronic hemolytic diseases and healthy conditions, using human patient samples.
David Jang
University of Pennsylvania, PA·Medicine & Clinical Research
Define how mitochondrial injury, especially at Complex I, an energy-producing enzyme, contributes to brain, heart and microcirculation damage in a rodent model of acute and chronic organophosphate poisoning.
The school
University of Maryland, Baltimore: 23 labs on PI Pages, $1.5B a year on research, 79 research doctorates a year.
Reach out
A start for your email. Fill in the brackets.