Welcome to the Maves Lab
The Maves lab investigates skeletal muscle and heart development, with the goal of making discoveries that lead to new treatments for muscular dystrophy and heart disorders. We use the zebrafish as an animal model because of advantages for genetic manipulations, in vivo imaging and drug screening.
We currently have three main projects:
- We are using zebrafish (and also mice) to understand the mechanisms of skeletal muscle fiber-type differentiation.
- We are using a zebrafish model of Duchenne muscular dystrophy (the dmd mutant strain) to investigate new drug therapies for DMD. In particular, we want to take advantage of the fish model to identify potential combination drug therapies that are beneficial for DMD.
- We are using CRISPR-Cas9 genome editing in zebrafish to engineer mutations in genes that have been implicated in human congenital heart defects. Our goal is to gain insight into the functions of these genes in heart development.
Understanding skeletal muscle fiber-type differentiation
One focus of our lab is understanding the mechanisms behind how skeletal muscle cells differentiate into a specific muscle fiber type, either fast twitch or slow twitch. We are using zebrafish and mouse models to study the functions of new factors, such as Pbx homeodomain transcription factors, and how they control muscle fiber-type development.
Certain muscular dystrophies preferentially affect either fast or slow twitch muscle fibers. In human and mouse models of Duchenne muscular dystrophy (DMD), fast muscle fibers are more susceptible to damage than slow fibers. It is not clear how fiber-type identity confers susceptibility or resistance to muscular dystrophy. A goal of this project is to test a fundamental hypothesis: that factors that promote slow muscle differentiation will ameliorate the effects of DMD. Recent studies, including work from our lab, now create an opportunity to directly test whether fiber-type modulation is a viable therapeutic approach for muscular dystrophies. We take advantage of zebrafish models to address whether factors that regulate fiber-type differentiation enhance or suppress the zebrafish dmd muscle degeneration phenotype. Our approach is to manipulate fiber-type regulators that function early in development in dmd zebrafish embryos. We are also working to identify new epigenetic factors that regulate muscle fiber type. We are screening epigenetic chemicals for their abilities to enhance or suppress the zebrafish dmd phenotype. We expect that this project will identify genetic and epigenetic regulators of muscle fiber-type identities that confer susceptibility or resistance to muscular dystrophy. This project is aimed at an ultimate goal of manipulating skeletal muscle fiber type as a treatment for muscular dystrophy.
Using zebrafish to identify drug combination therapies and biomarkers for Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is a muscle wasting disease caused by mutations in the DMD gene, which encodes dystrophin. There are presently no cures. The current standard of care is corticosteroid treatment, which delays the progression of skeletal muscle and cardiac dysfunction but also has serious side effects. The potential for novel drug combination therapies for DMD has not been fully explored. The long-term goal of this project is to establish zebrafish as a preclinical translation model for evaluating optimal DMD drug combination therapies. Our hypothesis is that the zebrafish dmd model can be used to identify both beneficial drug combinations that ameliorate DMD and mRNA biomarkers associated with this amelioration. Zebrafish offer several advantages for this study, in particular that both cardiac and skeletal muscle phenotypes and biomarkers can be easily monitored. We are systematically evaluating a set of drug combination therapies using the zebrafish dmd model. We are also testing for mRNA biomarkers associated with disease progression and drug-induced disease amelioration using qRT-PCR and RNA-seq on dmd zebrafish. A potential impact of this project will be the identification of novel drug combinations that are beneficial for DMD. Because we are testing drugs that are already being used in the clinic or in clinical trials, our findings could potentially be rapidly incorporated into drug-combination therapies for patients.
Using zebrafish and CRISPR-Cas9 to understand the mechanisms of heart development and the genetics of congenital heart defects
While the genetic and molecular basis for congenital heart defects remains largely unknown, intensive studies have uncovered prominent roles for transcription and chromatin-modifying factors in heart development and disease. Our long-term goal with this project is to achieve a precise understanding of the transcriptional mechanisms underlying early heart development. Our group has shown that Pbx and Meis homeodomain transcription factors are critical regulators of heart development in zebrafish. However, the mechanisms underlying Pbx/Meis function in heart development and congenital heart defects are not understood. We are using CRISPR-Cas9 genome editing to engineer mutations in zebrafish pbx and meis genes to determine their functions in heart development. We are particularly interested in understanding how Pbx and Meis factors regulate the differentiation of cardiomyocytes. Because the transcriptional regulation of cardiomyocyte differentiation is highly conserved, our zebrafish work will have relevance for human heart development and disease. In addition, we are using CRISPR-Cas9 to engineer zebrafish models of human genetic variants associated with congenital heart defects. Our studies will improve our understanding of how transcriptional regulatory factors like Pbx and Meis contribute to heart development and congenital heart defects. Our work could provide better understanding of the genetics of congenital heart defects. Our work may also guide the use of Pbx/Meis for programming cells into cardiomyocytes for the repair of congenital heart defects.
- Talbot J, Maves L. Skeletal muscle fiber type: using insights from muscle developmental biology to dissect targets for susceptibility and resistance to muscle disease. Wiley Interdiscip Rev Dev Biol. 2016 Jul;5(4):518-34. PMID 27199166
- Kao RM, Rurik JG, Farr GH 3rd, Dong XR, Majesky MW, Maves L. Pbx4 is required for the temporal onset of zebrafish myocardial differentiation. J Dev Biol. 2015;3(4):93-111. PMID 26770887
- Fong AP, Yao Z, Zhong JW, et al. Conversion of MyoD to a neurogenic factor: binding site specificity determines lineage. Cell Rep. 2015 Mar 31;10(12):1937-46. PMID 25801030
- Maves L. Recent advances using zebrafish animal models for muscle disease drug discovery. Expert Opin Drug Discov. 2014 Sep;9(9):1033-45. PMID 24931439
- Johnson NM, Farr GH 3rd, Maves L. The HDAC inhibitor TSA ameliorates a zebrafish model of Duchenne muscular dystrophy. PLoS Curr. 2013 Sep 17;5. PMID 24459606
- Yao Z, Farr GH 3rd, Tapscott SJ, Maves L. Pbx and Prdm1a transcription factors differentially regulate subsets of the fast skeletal muscle program in zebrafish. Biol Open. 2013 Apr 8;2(6):546-55. PMID 23789105
Lisa Maves, PhD, is a principal investigator at Seattle Children’s Research Institute and an assistant professor of pediatrics at the University of Washington School of Medicine. She received her PhD from the University of Washington and completed postdoctoral research at the University of Oregon and at Fred Hutchinson Cancer Research Center, where she was a staff scientist before joining Seattle Children's Research Institute in 2012. Her work at Seattle Children’s focuses on basic research on heart and muscle development and disease, with a particular interest in muscular dystrophy and congenital heart disorders.
- Lisa Maves, PhD’s researcher profile
- Email Lisa Maves, PhD.
- Partnership opportunity: Zebrafish as a preclinical model for evaluating DMD drug therapies and biomarkers
Faces of Research
Dr. Maves discusses the lab’s work and some of the goals of our research in this video:
Dr. Maves talks about her work and her interest in science in this video: