Stem cells and cardiovascular development

First author publications resulting from Palpant lab honours projects:

• Mizikovsky D, Sanchez MN, Nefzger CM, Cuellar Partida G*, Palpant NJ*. Organization of gene programs revealed by unsupervised analysis of diverse gene–trait associations. Nucleic Acids Research, 2022; Aug 26;50(15):e87. *For this study, Dalia Mizikovsky received the Michael F. Hickey Memorial Honours Prize, The University of Queensland (2020)
• Sinniah E, Wu Z, Shen S, Naval-Sanchez M, Chen X, Lim J, Helfer A, Iyer A, Tng J, Lucke AJ, Reid RC, Redd MA, Nefzger CM, Fairlie DP, Palpant NJ. Temporal perturbation of histone deacetylase activity reveals a requirement for HDAC1-3 in mesendoderm cell differentiation. Cell Reports. 2022 May 17;39(7):110818.

Available Honours projects

To apply for an Honours project with the Palpant Lab, please send an expression of interest to the relevant Supervisor(s) ensuring you include a copy of your CV and academic transcript.

Engineering cell identity: Using human pluripotent stem cells to program cells with customised functions not seen in the natural world

Supervisor: Dr Nathan Palpant (n.palpant@uq.edu.au)

This project seeks to explore the frontier of cell engineering by utilizing pluripotent stem cells as a model system. These stem cells, known for their ability to differentiate into any cell type, will be manipulated to remove the epigenetic barriers that conventionally restrict cell identity. By transcending these intrinsic limitations, the study aims to engineer cells with functions and characteristics not observed in the natural world. The potential impact of this work extends not only to fundamental discovery science, where it may open new avenues in understanding cellular differentiation and control, but also to translational applications. Innovations in synthetic biology could emerge from this research, impacting areas such as tissue engineering, regenerative medicine, and the development of novel therapeutic strategies.

Targeting stress and protein quality control pathways in skeletal muscle disease

Supervisors: Amy Hanna (a.hanna@imb.uq.edu.au); A/Prof Nathan Palpant (n.palpant@uq.edu.au)

Skeletal muscle is an active, highly dynamic tissue that is constantly building new proteins to perform integral muscle activities like contraction, temperature regulation and energy expenditure.  In healthy muscle, misfolded proteins are removed before they can affect cellular health but in some muscle diseases these misfolded proteins remain in the cell and aggregate, causing activation of stress pathways. How these misfolded proteins affect the ability of muscle to function is poorly understood. This project will examine the factors that regulate protein folding in skeletal muscle and determine how the accumulation of misfolded proteins affects muscle contraction and muscle size. We will also determine if these stress pathways can be targeted to treat congenital myopathy by testing novel pharmacological agents in models of human muscle disease. 

Understanding acid sensitivity of the heart: identifying genes and drugs that block the injury response of the heart during ischemic stress

Supervisor: Dr Nathan Palpant (n.palpant@uq.edu.au)

This project aims to explore heart injury mechanisms that occur under low-oxygen conditions. Drawing insights from studies on high altitude adaptation, the project aims to uncover genetic factors that may confer tolerance to hypoxic environments. These discoveries are anticipated to facilitate the identification of novel genetic targets that can be employed in the treatment of patients suffering from heart attacks. Utilizing human pluripotent stem cells, ischemia will be modeled in vitro to test new genes or pharmacological agents that prevent cell death under acute stress conditions. Given that heart attacks represent the leading cause of death globally, the findings of this project will offer innovative strategies to alleviate the substantial burden associated with cardiac diseases. 

Unlocking Vascular Control: Investigation of a Novel Gene Regulating Blood Pressure for Therapeutic Development

Supervisor: Dr Nathan Palpant (n.palpant@uq.edu.au)

This project aims to study a newly discovered gene that plays a crucial role in controlling vascular development and regulating blood pressure. We aim to understand the mechanisms and functions of this gene to open new avenues for the development of novel therapeutics specifically tailored for blood pressure management. Utilizing an integrative approach that combines animal models, stem cell models, and genetics, the study will dissect the pathways and functions of this gene. The project will contribute to the expanding body of knowledge surrounding genetic control of vascular function, thus enhancing our comprehension of blood pressure regulation at a molecular level. The outcomes may lead to the creation of new drugs, providing approaches to treat hypertension and other blood pressure-related diseases. 

First author publications resulting from Palpant lab PhD projects:

• Wu, Z, Shen, S, Mizikovsky, D, Cao, Y, Naval-Sanchez, M, Tan, SZ, Alvarez, YD, Sun, Y, Chen, X, Zhao, Q, Kim, D, Yang, P, Hill, TA, Jones, A, Fairlie, DP, Pébay, A, Hewitt, AW, Tam, PPL, White, MD, Nefzger, CM, Palpant, NJ. Dose escalation of Wnt stimulation during the exit from pluripotency identifies tranilast as a small molecule regulator of cardiac mesoderm differentiation. Developmental Cell, 2024, in press.
• Friedman, CE, Cheetham, SW, Negi, S, Mills, RJ , Ogawa, M, Redd, MA, Chiu, HS, Shen, S, Sun, Y, Mizikovsky, D, Bouveret, R, Chen, X, Voges, H, Paterson, S, De Angelis, JE, Andersen, SB, Cao, Y, Wu, Y, Jafrani, YMA, Yoon, S, Faulkner, GJ, Smith, KA, Porrello, E, Harvey, RP, Hogan, BM , Nguyen, Q, Zeng, J, Kikuchi, K, Hudson, JE , Palpant, NJ. HOPX associated molecular programs control cardiomyocyte cell states underpinning cardiac structure and function. Developmental Cell, 2024, 59 (1), 91-107.e1.
• Sun Y, Shim WJ, Shen S, Sinniah E, Pham D, Su Z, Mizikovsky D, White MD, Ho JWK, Nguyen Q, Bodén M*, Palpant NJ*. Inferring cell diversity in single cell data using consortium-scale epigenetic data as a biological anchor for cell identity, Nucleic Acids Research, 2023; Jun 23;51(11):e62.
• Shen S, Sun Y, Matsumoto M, Shim WJ, Sinniah E, Wilson SB., Werner T, Wu Z, Bradford ST., Hudson J, Little MH., Powell J, Nguyen Q, and Palpant NJ. Integrating single-cell genomics pipelines to discover mechanisms of stem cell differentiation. Trends in Molecular Medicine. 2021, 27, 1135-1158.
• Mizikovsky D, Sanchez MN, Nefzger CM, Cuellar Partida G*, Palpant NJ*. Organization of gene programs revealed by unsupervised analysis of diverse gene–trait associations. Nucleic Acids Research, 2022; Aug 26;50(15):e87. *For this study, Dalia Mizikovsky won the Queensland Cardiovascular Research Network PhD top up scholarship (2022)
• Sinniah E, Wu Z, Shen S, Naval-Sanchez M, Chen X, Lim J, Helfer A, Iyer A, Tng J, Lucke AJ, Reid RC, Redd MA, Nefzger CM, Fairlie DP, Palpant NJ. Temporal perturbation of histone deacetylase activity reveals a requirement for HDAC1-3 in mesendoderm cell differentiation. Cell Reports. 2022 May 17;39(7):110818. *For this study, Enakshi Sinniah won the Children's Hospital Foundation PhD top up scholarship
• Shim WJ, Sinniah E, Xu J, Vitrinel B, Alexanian M, Andreoletti G, Shen S, Sun Y, Balderson B, Boix C, Peng G, Jing N, Wang Y, Kellis M, Tam P, Smith A, Piper M, Christiaen L, Nguyen Q, Boden M**, Palpant NJ**. Conserved epigenetic regulatory logic infers genes governing cell identity. Cell Systems. 11, 625-639 e613 (2020). *This study resulted in Woo Jun Shim wining the Emma Whitelaw ECR Publication Award – Australian Epigenetics Alliance (2022).
• Friedman CE, Nguyen Q, Lukowski SW, Chiu HS, Helfer A, Miklas J, Suo SS, Han JDJ, Osteil P, Peng G, Jing N, Baillie GJ, Senabouth A, Christ AN, Bruxner TJ, Murry CE, Wong ES, Ding J, Wang Y, Hudson J, Ruohola-Baker H, Bar-Joseph Z, Tam PPL, Powell JE**, and Palpant NJ**. Single-Cell Transcriptomic Analysis of Cardiac Differentiation from Human PSCs Reveals HOPX-Dependent Cardiomyocyte Maturation. Cell Stem Cell.  2018 Oct 4;23(4):586-598.e8.

Available PhD projects

Please see below for available PhD projects with the Palpant Lab. If you are interested in any of the below, email the Principal Advisor ensuring the project title is in the subject line and your latest CV is attached. Once you have confirmation that they will endorse you for your project, you may officially apply via the UQ Application Portal.

Parsing the genome into functional units to understand the genetic basis of cell identity and function

Principal Advisor: Associate Professor Nathan Palpant (n.palpant@uq.edu.au)

Associate Advisors: Dr Woo Jun Shim (w.shim@uq.edu.au), Dr Sonia Shah (sonia.shah@imb.uq.edu.au), Dr Bastien Llamas (University of Adelaide)

The billions of bases in the genome are shared among all cell types and tissues in the body. Understanding how regions of the genome control the diverse functions of cells is fundamental to understanding evolution, development, and disease. We recently identified approaches to define diverse biologically constrained regions of the genome that appear to control very specific cellular functions. This project will evaluate how these biologically constrained regions of the genome have influenced evolutionary processes, evaluate their regulatory basis in controlling the identity and function of cells, and analyse the promiscuity of cross-talk between different biologically constrained regions. The project will also study how these genomic regions impact disease mechanisms by evaluating how disease-associated variants in different regions influence survival of patients with cancer and assessing whether these regions are associated with identifying causal disease variants in human complex trait data. The project will involve significant collaborative work with industry partners and researchers across Australia with the goal of providing critical insights into fundamental mechanisms of genome regulation.

Using genetic adaptation to high altitude to discover mechanisms regulating acute responses to ischemia

Principal Advisor: Associate Professor Nathan Palpant (n.palpant@uq.edu.au)

Associate Advisors: Professor Glenn King (glenn.king@imb.uq.edu.au), Dr Sonia Shah (sonia.shah@imb.uq.edu.au) and Dr Toby Passioura (University of Sydey)

Human populations living in high-altitude hypoxic environments have shown generational gene adaptations compared to lowland cohorts. These extreme stresses result in adaptive changes in the genome to maintain cell viability and function. We hypothesise that genes adapted to high altitude provide a unique approach for discovering novel mechanisms to protect organs from acute ischemic stresses like heart attacks. My laboratory is studying the genetics of lowland versus highland populations in China and Central America and using human pluripotent stem cells (hiPSCs) to study genes selected for high-altitude survival. Preliminary single-cell RNA-seq analysis of differentiated European vs. Han Chinese iPSCs revealed a unique gene expression signature for hypoxia pathways shared by the Han Chinese iPSCs with high altitude-associated haplotypes. We have also identified the gene encoding TMEM206, an acid-sensing ion channel, as a candidate “high-altitude gene”. Genetic knockout of TMEM206 reduces cardiomyocyte sensitivity to ischemia. These data and cell tools are a rich resource for discovering genes under adaptive pressure that could in turn reveal mechanisms and drug targets for protecting the heart against acute injury. This project will use iPSCs selected by known high-altitude haplotypes and compared using in vitro ischemia assays to measure cardiomyocyte cell death. We will analyse haplotype differences in differentiated cardiomyocytes by RNA-seq to identify gene expression programs associated with high altitude-adapted genotypes. We will then use the Broad Institute Connectivity MAP, which links drug perturbations to gene expression changes, to identify novel drugs that induce a “high altitude” gene expression profile in cardiomyocytes. Candidate drugs will be tested in wildtype cells (lacking the high-altitude haplotypes) to assess efficacy in reducing cell death during acute ischemic stress. Using our CRISPR gene methods, we will also knockout candidate “high-altitude genes” identified from statistical genetic studies and assay them using in vitro acidosis/ischemia models. For genes such as TMEM206 that show a role in mediating cardiomyocyte cell death, we will work with associate supervisors Glenn King (UQ) and Toby Passioura (U Sydney) in using the RaPID screen to discover cyclic peptides that inhibit stress-sensitive ion channels. 

De-risking the drug development pipeline by finding biomarkers of drug action

Principal Advisor: Associate Professor Nathan Palpant (n.palpant@uq.edu.au)

Associate Advisors: Dr Sonia Shah (sonia.shah@imb.uq.edu.au) and Professor Glenn King (glenn.king@imb.uq.edu.au)

Greater than 90% of drugs fail to advance into clinical approval. Genetic evidence supporting a drug-target-indication can improve the success by greater than 50%. This project aims to make use of consortium-level data resources (UKBiobank, Human Cell Atlas, ENCODE etc) to identify genetic links between genetic targets and phenotypes to help facilitate the translation of drugs from healthy individuals (Phase 1 clinical trial assessing safety) into sick patients (Phase 2 clinical trial assessing efficacy). Finding orthogonal biomarkers of drug action in healthy individuals is critical to de-risk drug dosing when transitioning from Phase 1 to Phase 2 trials. Using ASIC1a as a candidate drug being developed to treat heart attacks, this project will develop a functionally validated computational pipeline to predict orthogonal biomarkers of ASIC1a inhibitor drug action in healthy individuals to help inform dosing in human clinical trials. Computationally predicted biomarkers will be validated using genetic knockout animals and pharmacological inhibitors of ASIC1a. Collectively, this project will help develop proof-of-principle computational pipeline for orthogonal biomarker prediction of drug targets in the human genome.

Developing new therapeutic and diagnostic tools for tissue ischemia

Principal Advisor: Associate Professor Nathan Palpant (n.palpant@uq.edu.au)

Associate Advisors: Professor Glenn King (glenn.king@imb.uq.edu.au)

The research project will test the hypothesis that acid sensing ion channel 1a (ASIC1a) mechanistically underpins ischemia-induced injury across diverse organs and thus provides both a diagnostic marker and a therapeutic target for tissue ischemia. While ischemic injuries to the heart and brain in the form of heart attack and stroke are the most significant contributors to the global burden of disease, all organs are susceptible to ischemic injury whether in the context of patient care or during the procurement and storage of organs for transplantation. My laboratory aims to accelerate the diagnosis and prevention of organ damage due to tissue ischemia. This project stems from our elucidation of ASIC1a as a novel target for ischemic injuries and our discovery of Hi1a, the most potent known inhibitor of this channel, from venom of an Australian funnel-web spider. In preclinical studies we showed that Hi1a is a safe and potent therapeutic that reduces brain injury after stroke, improves recovery after a heart attack, and enhances the performance of donor hearts procured for transplantation. These remarkable therapeutic properties stem from Hi1a’s ability to protect cells from ischemic injury by inhibiting ASIC1a. Exciting preliminary data demonstrating that Hi1a interacts only with ASIC1a in tissue regions experiencing acute ischemia and not in healthy or the remote zone of injured tissue. This presents a unique opportunity to develop Hi1a as a diagnostic tool (theranostic) to measure the progression of ischemic injuries using clinical imaging methods. This project will develop peptidic ASIC1a inhibitors as a diagnostic marker of tissue ischemia. We will develop radiolabelled peptides that bind to ASIC1a with high affinity  to image the progression of organ ischemia in vivo using positron emission tomography-magnetic resonance imaging (PET-MRI). The project will also determine the temporal-spatial activation of ASIC1a-Hi1a interactions across organ systems in response to acute acidosis. Using a murine model of global hypercapnic acidosis, we will determine ASIC1a-Hi1a interactions at a tissue and sub-cellular level during acute ischemic stress to reveal the broader therapeutic landscape for ASIC1a inhibitors. The over-arching goal of this project is to understand the biology of ASIC1a stress response mechanisms across diverse organ systems. 

Postdoctoral fellows will be recruited based on funding availability. Individuals interested in a position can contact A/Prof Palpant (n.palpant@uq.edu.au) directly to assess current opportunities. 

First author publications resulting from Palpant lab postdoc projects:

• Redd MA, Yoshikawa Y, Khan N, Waqar M, Saez NJ, Outhwaite JE, Russell JS, Hanna AD, Chiu HS, Er SY, Butcher NJ, Mardon K, Fraser JF, Smythe ML, Rash LD, Thomas WG, King GF*, Reichelt ME*, Palpant NJ*. Acid-sensing ion channel 1a blockade reduces myocardial injury in rodent models of myocardial infarction. European Heart Journal, in press.
• Sun Y*, Shim WJ*, Shen S, Sinniah E, Pham D, Su Z, Mizikovsky D, White MD, Ho JWK, Nguyen Q, Bodén M*, Palpant NJ*. Inferring cell diversity in single cell data using consortium-scale epigenetic data as a biological anchor for cell identity, Nucleic Acids Research, 2023; Jun 23;51(11):e62.
• Redd MA, Scheuer SE, Saez NJ, Yoshikawa Y, Chiu HS, Gao L, Hicks M, Villanueva JE, Joshi Y, Chow CY, Cuellar-Partida G, Peart JN, See Hoe LE, Chen X, Sun Y, Suen JY, Hatch RJ, Rollo B, Alzubaidi MAH, Maljevic S, Quaife-Ryan GA, Hudson JE, Porrello ER, White MY, Cordwell SJ, Fraser JF, Petrou S, Reichelt ME, Thomas WG, King GF*, Macdonald PS*, Palpant NJ*. Therapeutic inhibition of acid sensing ion channel 1a recovers heart function after ischemia-reperfusion injury.Circulation. 2021;144:947–960. *This study formed the foundational data for Infensa Bioscience to commercialise ASIC1a inhibitors for treatment of myocardial infarction. Meredith received multiple awards for this including Ralph Reader Basic Science Prize of Cardiac Society of Australia and New Zealand (CSANZ) (2021) and Institute for Molecular Bioscience Impact Award for Paper of the Year (2021)

HAYA Therapeutics is a precision therapeutics company that discovers and develops innovative tissue- and cell-selective genomic medicines for fibrotic diseases and other serious health conditions associated with aging, including cancer. The Palpant laboratory is embedded in the company’s discovery engine focusing on identifying long non-coding RNAs (lncRNAs) within the “dark matter” of the human genome to identify key tissue and cell-specific drivers of fibrosis and other disease processes. The long term goal is to develop novel targets and drug candidates with the potential for greater efficacy and safety than existing treatments. HAYA’s lead therapeutic candidate is an antisense molecule targeting Wisper, a cardiac-enriched master driver of fibrosis, which has shown in preclinical testing the ability to halt and potentially reverse the fibrotic processes underlying heart failure.

Relevant Grants

• Assessing the role of noncoding RNAs in fibroblast remodeling after cardiac injury. Grant # 31003A_182322. Swiss National Foundation.
• Commercial contract with HAYA Therapeutics, Switzerland. Uniquest AG-024694. 2020-2022

Relevant Publications
Shim WJ, Sinniah E, Xu J, Vitrinel B, Alexanian M, Andreoletti G, Shen S, Sun Y, Balderson B, Boix C, Peng G, Jing N, Wang Y, Kellis M, Tam P, Smith A, Piper M, Christiaen L, Nguyen Q, Boden M**, Palpant NJ**. Conserved epigenetic regulatory logic infers genes governing cell identity. Cell Systems. 11, 625-639 e613 (2020).

The Palpant laboratory is working with Merck to commercialise a method for barcoding human cells with proprietary barcodes that enables scalable multiplexed single cell RNA-seq. The platform provides unique capabilities for discovery exceeding design limits of existing commercially available barcoding methods. It enables 100 trillion possible unique barcode options to customise complexity and scale of multiplexing, has no sample handling requirements between cell isolation and single cell capture pipelines, involves simple workflow for amplifying barcode library to enhance data quality, and is compatible with any computational demultiplexing method.

The approach expands experimental design options beyond limitations of existing external barcoding. It provides the ability to scale barcoding of any human cell type to maximise data output with current best-practice capture efficiencies, multiplexed analysis of gene, drug, signalling, or other perturbations at scale, parameter testing protocol development such as disease modelling or cell differentiation assays, analysis of high-resolution time-course assays, and dissecting cell-cell interactions by cell mixing assays such as organoid models.

Relevant Grants

• Merck Research Grant. 2021-2022

We are developing methods for statistical inference between multiple imaging and cellular data for predictive computational models. Our goal is identify complex biomarkers, specifically joint imaging-molecular markers, and causal inference methods to identify mechanism of actions to predict therapeutic effects across biological models that can be applied to preclinical in-vitro screening data and retrospective clinical data.

Relevant Grants

• TRIAGE: A disease agnostic computational and modelling platform to accelerate variant classification. Medical Research Future Fund Genomics Health Futures Mission. APP2016033. 2022-2025

Relevant Publications
Shim WJ, Sinniah E, Xu J, Vitrinel B, Alexanian M, Andreoletti G, Shen S, Sun Y, Balderson B, Boix C, Peng G, Jing N, Wang Y, Kellis M, Tam P, Smith A, Piper M, Christiaen L, Nguyen Q, Boden M**, Palpant NJ**. Conserved epigenetic regulatory logic infers genes governing cell identity. Cell Systems. 11, 625-639 e613 (2020).

Mizikovsky D, Sanchez MN, Nefzger CM, Cuellar Partida G*, Palpant NJ*. Organization of gene programs revealed by unsupervised analysis of diverse gene–trait associations. Nucleic Acids Research, 2022; Aug 26;50(15):e87

Work by Dr Palpant on iPSC genome engineering and differentiation protocols resulted in a licensed patent (US Patent 10,612,002; 2020) on derivation of hPSCs-endothelial cells. This patent and seminal studies on regenerating the mammalian heart with iPSC-derived heart muscle (Nature) formed the basis for Sana Biotechnology (USA; USD $700M series A VC investment in 2019). The Palpant group is working with Sana CSO Professor Charles Murry to advance methods that control cell differentiation and improve engraftment of cells during transplantation.

Relevant Grants

• Induced pluripotent stem cell derived cardiomyocytes: a new therapy for "no-option" end stage heart failure. Medical Research Future Fund Stem Cell Therapies Mission. APP2007625. 2021-2025.
• Global Strategy and Partnerships Award, The University of Queensland, 2017, 2019

Relevant Publications

Friedman CE, Nguyen Q, Lukowski SW, Chiu HS, Helfer A, Miklas J, Suo SS, Han JDJ, Osteil P, Peng G, Jing N, Baillie GJ, Senabouth A, Christ AN, Bruxner TJ, Murry CE, Wong ES, Ding J, Wang Y, Hudson J, Ruohola-Baker H, Bar-Joseph Z, Tam PPL, Powell JE**, and Palpant NJ**. Single-Cell Transcriptomic Analysis of Cardiac Differentiation from Human PSCs Reveals HOPX-Dependent Cardiomyocyte Maturation. Cell Stem Cell.  2018 Oct 4;23(4):586-598.e8.

Palpant NJ*, Pabon L, Friedman CE, Roberts M, Hadland B, Zaunbrecher RJ, Bernstein I, Zheng Y, Murry CE. Generating high-purity cardiac and endothelial derivatives from patterned mesoderm using human pluripotent stem cells. Nature Protocols, 2017 Jan;12(1):15-31.

Chong JJ, Yang X, Don CW, Minami E, Liu Y, Weyers JJ, Mahoney WM, Van Biber B, Palpant NJ, Gantz J, Fugate JA, Muskheli V, Gough GM, Vogel KW, Astley CA, Hotchkiss CE, Baldessari A, Pabon L, Reinecke H, Gill EA, Nelson V, Kiem H, Laflamme MA, Murry  CE. Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate Non-Human Primate Hearts. Nature. 2014 Apr 30.

Shiba Y, Fernandes S, Zhu W, Kim J, Palpant NJ, Gantz J, Moyes KW, Muskheli V, Reinecke H, Van Biber B, Dardas T, Mignone JL, Izawa A, Hanna R, Viswanathan M, Gold JD, Kotlikoff MI, Murry CE, Laflamme MA. Human ESC-Derived Cardiomyocytes Electrically Integrate and Suppress Arrhythmias in a Guinea Pig Infarct Model. Nature. 2012 Sep 13;489(7415):322-5.