Dr. Heather Flanagan-Steet
Active Research Projects
Dr. Flanagan-Steet's research has largely focused on defining the mechanisms governing early tissue development. This has ranged from investigating
how neuromuscular synapses form to development of the embryonic heart and craniofacial skeleton. Over the last thirteen years Dr. Flanagan-Steet’s
efforts have centered on defining the molecular and cellular mechanisms underlying pathogenesis of rare genetic diseases. This has included
several lysosomal storage disorders (LSDs) as well as the congenital disorders of glycosylation (CDGs). Her work on genetic diseases has largely
involved generating zebrafish models to investigate gene function and disease pathogenesis. This work pioneered the use of zebrafish to model
rare inherited diseases, bringing new insight into the molecular initiators and mechanisms underlying pathogenesis of mucolipidosis II and
In her role as Director of Functional Studies, she works closely with the Divisions across the Center to advance our understanding of rare diseases.Our
team uses a combination of genetic, molecular, biochemical and microscopic approaches to answer questions of disease pathogenesis. We have
adapted both traditional and modern biochemical procedures to extend the utility of our zebrafish models to functionally understand the proteins
and genes we are studying. We are keenly interested in elucidated the full pathogenic cascade so that we may identify biochemical pathways
downstream of the causative genetic mutation that may be modulated for disease therapy. A summary of the current projects in her lab are shown
Disease models for the Congenital Disorders of Glycosylation (CDGs).
We are using zebrafish models of PMM2-CDG to identify pathogenic cascades driving cartilage and bone malformations, as well as neuromuscular
issues. We are currently addressing whether altered processing of specific proteins may initiate disease pathogenesis in these tissues. Our
group is also interested in defining how loss of subunits of the OST complex impact development. We are using TALENS and CRISPR-Cas9 tools
to generate zebrafish models of newly identified CDGs. Novel CDG models were initiated using patient-derived insight regarding CDG-associated
Defining the pathogenesis of lysosomal storage disorders.
Our group has been interested in understanding the pathogenic mechanisms associated with loss of carbohydrate-dependent lysosomal sorting for many
years. Using several zebrafish models of mucolipidosis II (MLII, I-cell), we have identified cathepsin proteases as key pathogenic initiators.
When mislocalized outside the cell these proteases can inappropriately act on numerous substrates, including growth factors such as TGFß, causing
abnormal chondrogenesis (see Figure 1). We continue to explore how extracellular cathepsin proteases influence normal and disease tissue development.
Our work has largely focused on abnormal cartilage development, but recent efforts include the congenital heart defects associated with MLII.
Within this work we are assessing novel nano-based therapies as a potential means to ameliorate disease pathology.
Figure 1: Mistargeted Cathepsins Sustain TGFß Signaling and Drive Abnormal Chondrogenesis
Disease Associated Malformations of Interest
- Flanagan-Steet H, Sias C, Steet R. (2009). Altered chondrocyte differentiation and extracellular matrix homeostasis in a zebrafish
model for mucolipidosis II. Am J Pathol. 175(5): 2063-2075. [PMC2774070]
- Petrey AC, Flanagan-Steet H, Johnson S, Fan X, De la Rosa M, Haskins ME, Nairn AV, Moremen KW, Steet R. (2012). Excessive
activity of cathepsin K is associated with cartilage defects in a zebrafish model of mucolipidosis II. Dis Model Mech. 5(2): 177-190.
- Flanagan-Steet H, Aarnio M, Kwan B, Guihard P, Petrey A, Haskins M, Blanchard F, Steet R. (2016). Cathepsin-mediated alterations
in TGFß-related signaling underlie disrupted cartilage and bone maturation associated with impaired lysosomal targeting. J Bone Miner Res.
31(3): 535-548. [PMC4808492]
- Flanagan-Steet H, Christian C, Lu PN, Aarnio-Peterson M, Sanman L, Archer-Hartmann S, Azadi P, Bogyo M, Steet RA. (2018) TGF-ß
Regulates Cathepsin Activation during Normal and Pathogenic Development. Cell Reports Mar 13;22(11):2964-2977. [PMID28724630].