Research

Research

Deep learning for cardiopulmonary MRI processing

One of the research objects in the lab is on the development of deep-learning algorithms for cardiopulmonary MRI processing, especially the development of unsupervised learning algorithms. We are interested in 2D and 3D cardiopulmonary MRI reconstruction, denoising, super-resolution and segmentation. In this objective, we have developed several algorithms such as G-SToRM, MoCo-SToRM, V-SToRM for real-time cardiopulmonary processing. These work on real-time cardiopulmonary processing wothe best paper award in 2020, and the best paper award finalist in 2021 at IEEE International Symposium on Biomedical Imaging (IEEE ISBI). We've also extended the above algorithms for better performances based on recent advances in deep learning such as the inclusion of Spatial Transformer Networks (STN), Implicit Neural Representations (INR), Graph Convolutional Network (GCN),Kernel method into the algorithms.

Placeholder 3D Lung MRI
Placeholder Multi-slice Cardiac Cine
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Pulse sequences development for cardiopulmonary MRI

The second line of research in the lab is on the development of novel fast 2D and 3D cardiopulmonary MRI pulse sequences for the care of patients with congenital and acquired heart diseases. This includes the development of fast 2D or 3D sequences for myocardial quantification, such as multi-tasking sequences, MR fingerprinting sequences. We are also interested in developing robust fast 3D MR angiography sequences, 3D lung sequences based on ultra-short echo time (UTE) sequences and non-contrast-enhanced 3D whole-heart sequences

react Non-Contrast-enhanced 3D whole-heart MRI

Translational cardiology research using advanced Cardiac imaging

Our lab also shows interest in developing new imaging biomarkers for congenital and acquired heart diseases. For example, we would like to develop new image biomarkers based on Magnetization transfer (MT) and Chemical exchange saturation transfer (CEST) for the quantification of myocardium without using Gadolinium-based contrast agents (GBCAs) for patients with acquired heart diseases. We are also interesting in developing new quantitative imaging biomarkers for the monitor of diseases progression for patients with congenital heart diseases, especially the patients with single-ventricle physiology.

Placeholder Quantify the level of water in the lung

Research projects at Zou Lab at UT Southwestern

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Research

Research

What is ubiquitin?

 

Ubiquitin is a small eukaryotic protein that is attached to aberrant proteins and promotes their degradation as a form of protein quality control. Ubiquitin is first bound by a ubiquitin activating enzyme (E1) in an ATP-dependent manner and transferred to a ubiquitin conjugating enzyme, or E2. The ubiquitin molecule is then covalently attached to its substrate through the action of an E3 ubiquitin ligase, which facilitates the transfer of ubiquitin from E2 to target protein. Additional ubiquitins can be added onto the first, forming a polyubiquitin chain. Polyubiquitylated substrates are directed to the proteasome, a large cellular protease, that degrades the substrate. Ubiquitin chains can be removed from substrates by deubiquitylase enzymes (DUBs), thus altering their fate.

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Ubiquitin-mediated orphan quality control sustains gene expression

 

Transcription factors are synthesized, assembled into a complex with binding partners, and help recruit cofactors to promote gene expression. Upon dissociation from DNA, these complexes are disassembled into individual subunits. Some of these "orphan" subunits are recognized as aberrant proteins by quality control E3 ubiquitin ligases (such as UBR5), and rapidly degraded to render complex disassembly irreversible. Remaining stable subunits can be reused in subsequent cycles of complex formation, use and disassembly. Thus, continuous turnover is necessary to remove "spent" transcription factors and sustain gene expression.

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Besides dimeric transcription factors, UBR5 also target subunits of elongation complexes and chromatin remodelers. Given that humans possess roughly 1,600 transcription factors alone, what other orphan E3 ubiquitin ligases might be involved in clearing chromatin to prepare for subsequent reinitiation? Moreover, how do cells regulate this process under different environmental conditions? Finally, can we harness the activity of orphan protein E3 ligases for therapeutic benefit?

Funding Provided By

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Videos

Videos

Dormant C. elegans oocytes with storage condensates (green) and membranes (red) labeled.

Dormant human oocyte surrounded by support cells.  Storage condensates (orange), mitochondria (red), and DNA (blue) are labeled.

Woodruff Lab videos

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Research

Inflammation is a rapid response of the body to microbial infections and tissue damage. Although inflammation protects against pathogenic assault and promotes healing, it can cause more damage than the inciting event if its magnitude and duration are not strictly controlled. Excessive and unrestrained inflammatory responses underlie various chronic inflammatory diseases, including autoimmunity and cancer.

Post-translational modifications mediated by ubiquitin conjugation play a critical regulatory role in immune cells. We have demonstrated earlier that the ubiquitin pathway proteins regulate T-cell tolerance and the deficiency of ubiquitin ligase Cbl-b, Itch and GRAIL cause defects in T-cell tolerance resulting in pathologic inflammation. This led to the concept that these ligases are dominant ‘toloregenic factors’ and can be targeted in inflammatory diseases and cancer immunotherapy.

The ubiquitin signal is interpreted on the basis of the number of attached ubiquitin chains and the topology of their linkage. A polyubiquitin chain is formed when one of the seven lysine residues in ubiquitin is linked to the C-terminal glycine of another ubiquitin. Although ubiquitin contains seven lysine residues, linkage generally occurs via either Lys48 (K48) or Lys63 (K63). K48-linked polyubiquitination mainly targets proteins for proteasomal degradation, whereas K63-linked polyubiquitination leads to nonproteasomal modifications, such as subcellular localization or protein-protein interactions. Similar to phosphorylation, protein ubiquitination is reversible, and removal of ubiquitin molecules is mediated by deubiquitinating enzymes such as Cyld.

We have shown that the ubiquitin ligase Itch forms a complex with Cyld that sequentially removes K63-linked ubiquitin chains and catalyzes K48-linked chains on Tak1, which is essential for attenuation of inflammatory signaling. Deficiency of Itch leads to severe lung cancer which was associated with elevated levels of tumor promoting cytokines such and IL-6 by the tumor associated macrophages. Our results further demonstrated that Itch regulates the expression of pro-inflammatory cytokines by modulating p38a phosphorylation. The pathologic consequences of losing this system in humans was highlighted by identification of a truncating mutation in Itch gene among Amish families which results in multi-organ inflammatory disorders. 

representative research highlights of the Poojary lab

The genetic deletion of Itch in mice leads to spontaneous colitis and increased growth of colon cancer. Mechanistically, we showed that Itch recognizes a conserved ‘PPXY’ motif within the transcription factor ROR-gt and regulates IL-17 expression. We further demonstrated that defects in the enzymatic activity of Itch in ulcerative colitis patients leads to elevated IL-17-mediated colonic inflammation and fibrosis. Furthermore, we recently showed that ROR-gt function is also regulated by its SUMOylation. 

We are now taking a bolder and more ambitious approach through a combination of systemic and biochemical approaches to discover new regulators of inflammation. Our research could lead to the development of novel therapeutic strategies for human inflammatory diseases and immunotherapy for cancer. 

Learn about Poojary Lab's research.

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