Ying Ge
· ProfessorUniversity of Wisconsin-Madison · Anatomy
Active 1986–2024
About
Ying Ge is a Professor in the Department of Cell and Regenerative Biology at the University of Wisconsin–Madison. Her research focuses on understanding the molecular and cellular mechanisms underlying cardiovascular diseases through systems biology approaches that utilize ultra high-resolution mass spectrometry-based comparative proteomics and metabolomics, combined with functional studies. Her work aims to elucidate disease mechanisms and develop new therapeutic strategies by analyzing proteins and metabolites, which are key molecular entities of the cell downstream of genes, in various biological contexts. Her research involves developing novel ultra high-resolution MS-based top-down comparative proteomics and metabolomics platforms to study the complexity and dynamics of the proteome and metabolome. She employs these technologies to identify, characterize, and quantify intact proteins and metabolites extracted from tissues, cells, and biofluids, revealing changes in response to stresses. Her current research directions include establishing a global map of cardiac myofilament protein modifications under normal and diseased conditions and evaluating the efficacy of stem cell therapies for heart failure treatment through integrated proteomics and metabolomics approaches. Her interdisciplinary work bridges chemistry, biology, and medicine, with the goal of advancing understanding of disease at the molecular level and fostering the development of early diagnosis, prevention, and treatment strategies for cardiovascular diseases.
Research topics
- Biology
- Chemistry
- Computer Science
- Computational biology
- Biochemistry
- Cell biology
- Immunology
- Molecular biology
- Genetics
- Cancer research
- Medicine
- Chromatography
- Bioinformatics
- Engineering
- Internal medicine
- Combinatorial chemistry
- Nanotechnology
- Stereochemistry
Selected publications
Oncogenesis · 2023 · 4 citations
- Molecular biology
- Biology
- Cell biology
Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated potent clinical efficacy in the treatment of hematopoietic malignancies. However, the application of CAR-T in solid tumors has been limited due in part to the expression of inhibitory molecules in the tumor microenvironment, leading to T-cell exhaustion. To overcome this limitation, we have developed a synthetic T-cell receptor (TCR) that targets programmed death-ligand 1 (PD-L1), a molecule that is widely expressed in various solid tumors and plays a pivotal role in T-cell exhaustion. Our novel TCR platform is based on antibody-based binding domain, which is typically a single-chain variable fragment (scFv), fused to the γδ TCRs (TCRγδ). We have utilized the T-cell receptor alpha constant (TRAC) locus editing approach to express cell surface scFv of anti-PD-L1, which is fused to the constant region of the TCRγ or TCRδ chain in activated T cells derived from peripheral blood mononuclear cells (PBMCs). Our results indicate that these reconfigured receptors, both γ-TCRγδ and δ-TCRγδ, have the capability to transduce signals, produce inflammatory cytokines, degranulate and exert tumor killing activity upon engagement with PD-L1 antigen in vitro. Additionally, we have also shown that γ-TCRγδ exerted superior efficacy than δ-TCRγδ in in vivo xenograft model.
High sensitivity top–down proteomics captures single muscle cell heterogeneity in large proteoforms
Proceedings of the National Academy of Sciences · 2023 · 66 citations
Senior authorCorresponding- Computer Science
- Computer Science
- Engineering
Single-cell proteomics has emerged as a powerful method to characterize cellular phenotypic heterogeneity and the cell-specific functional networks underlying biological processes. However, significant challenges remain in single-cell proteomics for the analysis of proteoforms arising from genetic mutations, alternative splicing, and post-translational modifications. Herein, we have developed a highly sensitive functionally integrated top-down proteomics method for the comprehensive analysis of proteoforms from single cells. We applied this method to single muscle fibers (SMFs) to resolve their heterogeneous functional and proteomic properties at the single-cell level. Notably, we have detected single-cell heterogeneity in large proteoforms (>200 kDa) from the SMFs. Using SMFs obtained from three functionally distinct muscles, we found fiber-to-fiber heterogeneity among the sarcomeric proteoforms which can be related to the functional heterogeneity. Importantly, we detected multiple isoforms of myosin heavy chain (~223 kDa), a motor protein that drives muscle contraction, with high reproducibility to enable the classification of individual fiber types. This study reveals single muscle cell heterogeneity in large proteoforms and establishes a direct relationship between sarcomeric proteoforms and muscle fiber types, highlighting the potential of top-down proteomics for uncovering the molecular underpinnings of cell-to-cell variation in complex systems.
Research Square (Research Square) · 2022
- Chemistry
- Cancer research
- Molecular biology
Abstract Chimeric antigen receptor (CAR)-T cells have shown potent clinical efficacy in the treatment of hematopoietic malignancies. However, much less has been achieved in solid tumors, in part due to the CAR-T cell exhaustion caused by inhibitory molecules in the tumor microenvironment. Given that PD-L1 is widely expressed in various tumor types and the PD1/PD-L1 axis plays a pivotal role in T cell exhaustion, we developed a novel platform using a single chain variable fragment (scFv) γδ-based TCR to target PD-L1 expressing tumors. We edited the TRAC locus in T cells and expressed an anti-PD-L1 scFv fused to the constant region of either the TCRδ or γ chain. We showed that the reconfigured γδ TCRs were capable of transducing signals once PD-L1 antigen was engaged by the scFv, leading to production of inflammatory cytokines, degranulation, and potent tumor killing activity both in vitro and in various xenograft solid tumor models. Surprisingly, we discovered that a new form of TCR, generated by fusing an scFv coding region to that of a single TCRγ chain, is sufficient to activate T cells and direct T cell functional activity. Moreover, in contrast to the classic TCRγδ, this new synthetic TCR appeared to transduce signals without complexing with endogenous CD3, which represents a new platform of cancer therapeutics.
Journal of the American Chemical Society · 2022 · 34 citations
- Computational biology
- Chemistry
- Stereochemistry
) biosynthetic gene cluster and stable isotope-feeding experiments helped illuminate the novel enzymology driving ecteinamine assembly as well the role of cluster collaborations or "duets" in producing such structurally complex agents. Finally, ecteinamines were found to bind nickel, cobalt, zinc, and copper, suggesting a possible biological role as broad-spectrum metallophores.
RBM20 phosphorylation and its role in nucleocytoplasmic transport and cardiac pathogenesis
The FASEB Journal · 2022 · 27 citations
- Cell biology
- Biology
- Molecular biology
Arginine-serine (RS) domain(s) in splicing factors are critical for protein-protein interaction in pre-mRNA splicing. Phosphorylation of RS domain is important for splicing control and nucleocytoplasmic transport in the cell. RNA-binding motif 20 (RBM20) is a splicing factor primarily expressed in the heart. A previous study using phospho-antibody against RS domain showed that RS domain can be phosphorylated. However, its actual phosphorylation sites and function have not been characterized. Using middle-down mass spectrometry, we identified 16 phosphorylation sites, two of which (S638 and S640 in rats, or S637 and S639 in mice) were located in the RSRSP stretch in the RS domain. Mutations on S638 and S640 regulated splicing, promoted nucleocytoplasmic transport and protein-RNA condensates. Phosphomimetic mutations on S638 and S640 indicated that phosphorylation was not the major cause for RBM20 nucleocytoplasmic transport and condensation in vitro. We generated a S637A knock-in (KI) mouse model (Rbm(20S637A)) and observed the reduced RBM20 phosphorylation. The KI mice exhibited aberrant gene splicing, protein condensates, and a dilated cardiomyopathy (DCM)-like phenotype. Transcriptomic profiling demonstrated that KI mice had altered expression and splicing of genes involving cardiac dysfunction, protein localization, and condensation. Our in vitro data showed that phosphorylation was not a direct cause for nucleocytoplasmic transport and protein condensation. Subsequently, the in vivo results reveal that RBM20 mutations led to cardiac pathogenesis. However, the role of phosphorylation in vivo needs further investigation.
Novel Strategies to Address the Challenges in Top-Down Proteomics
Journal of the American Society for Mass Spectrometry · 2021 · 192 citations
Senior authorCorresponding- Chemistry
- Computational biology
- Biochemistry
Top-down mass spectrometry (MS)-based proteomics is a powerful technology for comprehensively characterizing proteoforms to decipher post-translational modifications (PTMs) together with genetic variations and alternative splicing isoforms toward a proteome-wide understanding of protein functions. In the past decade, top-down proteomics has experienced rapid growth benefiting from groundbreaking technological advances, which have begun to reveal the potential of top-down proteomics for understanding basic biological functions, unraveling disease mechanisms, and discovering new biomarkers. However, many challenges remain to be comprehensively addressed. In this Account & Perspective, we discuss the major challenges currently facing the top-down proteomics field, particularly in protein solubility, proteome dynamic range, proteome complexity, data analysis, proteoform-function relationship, and analytical throughput for precision medicine. We specifically review the major technology developments addressing these challenges with an emphasis on our research group's efforts, including the development of top-down MS-compatible surfactants for protein solubilization, functionalized nanoparticles for the enrichment of low-abundance proteoforms, strategies for multidimensional chromatography separation of proteins, and a new comprehensive user-friendly software package for top-down proteomics. We have also made efforts to connect proteoforms with biological functions and provide our visions on what the future holds for top-down proteomics.
The Human Proteoform Project: Defining the human proteome
Science Advances · 2021 · 236 citations
- Computer Science
- Computational biology
- Computer Science
Proteins are the primary effectors of function in biology, and thus, complete knowledge of their structure and properties is fundamental to deciphering function in basic and translational research. The chemical diversity of proteins is expressed in their many proteoforms, which result from combinations of genetic polymorphisms, RNA splice variants, and posttranslational modifications. This knowledge is foundational for the biological complexes and networks that control biology yet remains largely unknown. We propose here an ambitious initiative to define the human proteome, that is, to generate a definitive reference set of the proteoforms produced from the genome. Several examples of the power and importance of proteoform-level knowledge in disease-based research are presented along with a call for improved technologies in a two-pronged strategy to the Human Proteoform Project.
Proceedings of the National Academy of Sciences · 2020 · 107 citations
Senior authorCorresponding- Biology
- Genetics
- Bioinformatics
= 16). We observed a complex landscape of sarcomeric proteoforms arising from combinatorial PTMs, alternative splicing, and genetic variation in HCM. A coordinated decrease of phosphorylation in important myofilament and Z-disk proteins with a linear correlation suggests PTM cross-talk in the sarcomere and dysregulation of protein kinase A pathways in HCM. Strikingly, we discovered that the sarcomeric proteoform alterations in the myocardium of HCM patients undergoing septal myectomy were remarkably consistent, regardless of the underlying HCM-causing mutations. This study suggests that the manifestation of severe HCM coalesces at the proteoform level despite distinct genotype, which underscores the importance of molecular characterization of HCM phenotype and presents an opportunity to identify broad-spectrum treatments to mitigate the most severe manifestations of this genetically heterogenous disease.
Chemical Science · 2020 · 152 citations
- Chemistry
- Chromatography
, native mass spectrometry. Sequence, post-translational modifications, ligand/metal binding, protein folding, and complex stoichiometry can thus all be probed directly. Here, we review recent developments in this new and exciting field of research. While this work is written primarily from a mass spectrometry perspective, it is targeted to all bioanalytical scientists who are interested in applying these methods to their own biochemistry and chemical biology research.
Journal of the American Society for Mass Spectrometry · 2020 · 125 citations
- Chemistry
- Computational biology
- Nanotechnology
The Consortium for Top-Down Proteomics (www.topdownproteomics.org) launched the present study to assess the current state of top-down mass spectrometry (TD MS) and middle-down mass spectrometry (MD MS) for characterizing monoclonal antibody (mAb) primary structures, including their modifications. To meet the needs of the rapidly growing therapeutic antibody market, it is important to develop analytical strategies to characterize the heterogeneity of a therapeutic product's primary structure accurately and reproducibly. The major objective of the present study is to determine whether current TD/MD MS technologies and protocols can add value to the more commonly employed bottom-up (BU) approaches with regard to confirming protein integrity, sequencing variable domains, avoiding artifacts, and revealing modifications and their locations. We also aim to gather information on the common TD/MD MS methods and practices in the field. A panel of three mAbs was selected and centrally provided to 20 laboratories worldwide for the analysis: Sigma mAb standard (SiLuLite), NIST mAb standard, and the therapeutic mAb Herceptin (trastuzumab). Various MS instrument platforms and ion dissociation techniques were employed. The present study confirms that TD/MD MS tools are available in laboratories worldwide and provide complementary information to the BU approach that can be crucial for comprehensive mAb characterization. The current limitations, as well as possible solutions to overcome them, are also outlined. A primary limitation revealed by the results of the present study is that the expert knowledge in both experiment and data analysis is indispensable to practice TD/MD MS.
Recent grants
MASH Explorer, a Comprehensive Software Environment for Top-Down Proteomics
NIH · $1.2M · 2018–2023
NIH · $2.0M · 2017
Deciphering Myofilament Modifications in Ischemic Cardiomyopathy
NIH · $2.8M · 2013–2025
Deciphering Myofilament Modifications in Ischemic Cardiomyopathy
NIH · $608k · 2013–2025
Top-Down Proteomics of Myofilaments in Heart Failure
NIH · $3.3M · 2011–2022
Frequent coauthors
- 47 shared
Zachery R. Gregorich
- 41 shared
David S. Roberts
Stanford University
- 39 shared
Wenxuan Cai
University of Calgary
- 37 shared
Yanlong Zhu
Beijing Institute of Fashion Technology
- 34 shared
Kyle A. Brown
University of Wisconsin–Madison
- 34 shared
Jeffery W. Walker
University of Arizona
- 33 shared
Ke‐Wu Yang
Northwest University
- 31 shared
Song Jin
University of Wisconsin–Madison
Labs
Education
- 2002
PhD, Chemistry and Chemical Biology
Cornell University
- 1997
BS, Chemistry
Peking University
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