Genetics and cell biology of cardiac development

Growing new organs – science fiction or science future?

The demand for organ donation increases every year, but the tissue available for donation remains static.

Dr Kelly Smith, during her PhD, was in the place where surgeons performed Australia’s first split liver transplant, trying to get more out of the organs that they had, and she thought ‘we should be making these’. She had found her research passion.

Dr Smith is a developmental biologist. Her research group is studying how the embryo forms a heart, when it begins as a single cell.

Research overview

“How does a heart grow? How do the first cells in an embryo develop to form a beating muscle that pumps blood throughout the body?” said Dr Smith.

“Understanding how the very first cells in an embryo become organ cells and understanding how that organ develops is the first step in creating or healing that organ.”

The focus of The Smith Groups research is the heart. Heart attack and cardiac arrest is the biggest killer in the western world. Heart rhythm dysfunction (such as tachycardia) affects 5% of the aged population and arrhythmias 2% of under 65-year-olds. Cardiomyopathy, where the heart becomes enlarged and thin, is responsible for many sudden deaths. Congenital heart defects affect 1 in 110 babies.

The Smith Group creates a version of a patient (an avatar) in Zebrafish with a particular gene mutation and monitors what is happening within the embryo. Through this process, with a very large sample of fish over a two-year period, the team and collaborators screened over 400 families of fish with gene mutations. They found six new genes that have never been described before.  

The discoveries have implications for valve repair, macular degeneration, wound healing, cancer growth and proper cardiac rhythm.

Research projects

Understanding the differentiation of the endocardium
2017-2020, ARC Discovery Project Grant
Collaborators: Dr Kelly Smith, Dr Nathan Palpant

Examining an extracellular matrix regulator required for cardiovascular development
2016-2019, NHMRC Project Grant
Collaborators: Dr Kelly Smith, Dr Mathias Francois, AProf Carol Wicking, Dr Enzo Porrello, Dr Ben Hogan

Functional and molecular characterisation of a novel regulator of angiogenesis
2013-2016, NHMRC Project Grant
Collaborators: Dr Kelly Smith, Dr Ben Hogan, Dr Mathias Francois

Research training opportunities

Research title: Genetics and cell biology of cardiac development

Summary of research interests: The function of the heart is to distribute blood around the body. It does so with high efficiency and without mixing oxygenated and deoxygenated blood. This is achieved by forming an elaborate and exact structure comprising of distinct chambers, delicate valves and septa all assembled with precision to ensure correct alignment with the major vessels. Any defects that occur during the formation of these elements result in structural defects, collectively known as congenital heart defects. In order to repair such defects, we must first understand how the heart is formed. During development, the heart begins as a simple symmetrical field of cells that undergoes differentiation, cellular migration, cellular transitions (such as endoMT) and cell shape changes. Using the translucent zebrafish model, we employ fluorescent transgenic reporter strains and genetic mutant lines to interrogate the cellular and genetic regulation of heart development. My research aims to understand how to build a heart.

Traineeships, honours and PhD projects include

  • Deciphering genetic pathways in cardiac valve development
  • Analysing cardiac progenitor cell migration during early heart development
  • Investigating cellular organisation in distinct cardiac compartments.

Dr Kelly Smith

+61 7 3346 2110
k.smith@imb.uq.edu.au


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Featured publications

  • De Angelis, Jessica E., Lagendijk, Anne K., Chen, Huijun, Tromp, Alisha, Bower, Neil I., Tunny, Kathryn A., Brooks, Andrew J., Bakkers, Jeroen, Francois, Mathias, Yap, Alpha S., Simons, Cas, Wicking, Carol, Hogan, Benjamin M. and Smith, Kelly A. (2017) Tmem2 regulates embryonic Vegf signaling by controlling hyaluronic acid turnover. Developmental Cell, 40 2: 123-136. doi:10.1016/j.devcel.2016.12.017

  • Capon, Samuel James, Baillie, Gregory , Bower, Neil, Da Silva, Jason Andrew, Paterson, Scott , Hogan, Ben , Simons, Cas and Smith, Kelly (2017) Utilising polymorphisms to achieve allele-specific genome editiing in zebrafish. Biology Open, 6 1: 125-131. doi:10.1242/bio.020974

  • Koltowska, Katarzyna, Paterson, Scott, Bower, Neil I., Baillie, Gregory J., Lagendijk, Anne K., Astin, Jonathan W., Chen, Huijun, Francois, Mathias, Crosier, Philip S., Taft, Ryan J., Simons, Cas, Smith, Kelly A. and Hogan, Benjamin M. (2015) mafba is a downstream transcriptional effector of Vegfc signaling essential for embryonic lymphangiogenesis in zebrafish. Genes and Development, 29 15: 1618-1630. doi:10.1101/gad.263210.115

View all Publications

Engagement and impact

The Smith Group was involved in the conducting the largest forward genetic screen in zebrafish ever done in Australia. They screened over 400 families and found 30 different genes, nine of which were new. The different mutants displayed a variety of morphological defects, including looping defects and failed chamber ballooning as well as poor function, such as cardiac arrhythmias and reduced heart contraction. Each of these mutant’s model different categories of cardiac disease, including congenital heart defects, dilated cardiomyopathy and cardiac arrhythmias. The types of genes affected in these mutants include known cardiac disease genes, such as Titan, as well as genes that encode regulators of the extracellular matrix (its production and degradation), cell-cell adhesion molecules, G-protein coupled receptors, transcription factors, ion channels and epigenetic modifiers. Studying these genes and mutants will provide insight into the mechanisms of disease and inform us for developing new treatment strategies.

For example, we identified two new mutant copies of a protein that breaks down the extracellular matrix. These mutants have improper cardiac valve development but also defective blood vessel development. Our analysis of how this protein degrades the extracellular matrix provides important information about the correct balance of the extracellular matrix in healthy valves and provides essential information if we are ever to synthesise or repair valves. An unexpected and unanticipated off-shoot of this research is discovering a role for this protein in blood vessel development. Understanding how to control blood vessel growth is important for developing methods to assist in wound repair and prevent diseases such as cancer metastases and macular degeneration. It is through this fundamental approach that novel discoveries are made and, frequently, where unexpected applications arise.

Partners and collaborators

Dr Kelly Smith collaborates broadly both within Australia and internationally.

Locally within Queensland, Dr Smith's collaborators include:

  • A/Prof Ben Hogan (IMB, UQ), on Forward genetic screening for zebrafish mutants
  • Dr Cas Simons (IMB, UQ), on Forward genetic screening for zebrafish mutants; NGS sequencing of CHD patients
  • A/Prof Mathias Francois (IMB, UQ), on Analysis of the cardiovascular system in mouse models
  • Professor Alpha Yap (IMB, UQ), on Generating cell biology tools to study cardiovascular morphogenesis
  • Dr Nathan Palpant (IMB, UQ), on Analysis of cardiac genes using zebrafish and human iPSCs
  • Professor Rob Parton (IMB, UQ), on Analysis of endosomal vesicles in zebrafish mutants
  • A/Prof Brett Collins (IMB, UQ), on Modelling patient mutations using the zebrafish model.

Nationally, Dr Smith's collaborators include:

  • Dr Enzo Porrello (MCRI, VIC), on Analysis of the cardiac regeneration using mouse models
  • Dr Michael Cheung (MCRI & RCH, VIC), on Sequencing CHD patients and creating zebrafish disease models
  • Prof Diane Fatkin (VCCRI, NSW), on Studying the role of Titin in cardiac development and function.

Internationally, Dr Smith's collaborators include:

  • Prof Jeroen Bakkers (Hubrecht Institute, Utrecht, Netherlands), on Analysis of zebrafish mutants
  • Prof Vincent Christoffels (AMC, Amsterdam, Netherlands), on Analysis of novel cardiac mutants
  • Prof Didier Stainier (Max Planck, Germany), on Analysing the cardiac development using novel transgenic reporters
  • Prof Naoki Mochizuki (NCVC, Japan), on Using novel transgenic tools to study early cardiac development
  • Prof Jan Huisken, (MGH, USA), on Analysing zebrafish cardiac function.
     

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Dr Kelly Smith

Dr Kelly Smith

Group Leader, Genomics of Development and Disease Division

  +61 7 3346 2053  
  k.smith@imb.uq.edu.au
  IMB Researcher Profile
  Centre for Cardiac and Vascular Biology


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  Group Leader

  • Dr Kelly Smith

    Group Leader, Genomics of Development and Disease Division
    Co-Director
    Centre for Cardiac and Vascular Biology
    Honorary Senior Fellow
    Institute for Molecular Bioscience

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