Advancing the Science

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February 18, 2019

Head to the Lab for the Treatments of Tomorrow

By Sara Tiner

Top: Paul Galardy, M.D.; Saad Kenderian, M.B., Ch.B.; Hu Li, Ph.D.
Bottom: Aleksey Matveyenko, Ph.D.; Christina Pabelick, M.D.; Hu Zeng, Ph.D.

Medical breakthroughs start in the lab with a phase of research called discovery science. It helps to understand how the body functions and how disease begins at the most basic level. That in turn provides insight into how whatever has gone wrong can be fixed.

To kick off the medical treatments of tomorrow, the Center for Biomedical Discovery is proud to support the following Discovery Science Award projects for 2019. These projects all promote innovative, cutting-edge discovery science teams that focus on understand the biological processes that contribute to human disease.

Investigating the role of a Gene in how a normal immune process goes bad

When we encounter infectious agents – either naturally or by vaccination – our immune system generates a highly selective defense against that particular danger. While essential for healthy life, this ability comes at a price: lymphomas. These cancers arise when immune cells edit their genetic material to customize and optimize the reaction to infections. Our work will uncover how the gene UCHL1 regulates the building of proteins in normal and cancerous immune cells in hopes of gaining a better understanding of how we might harness these events to enhance immunity – and fight cancer.

Primary Investigator:  Paul Galardy, M.D., Department of Pediatric and Adolescent Medicine;

Co-investigators:  Wenqian Hu, Ph.D., Department of Biochemistry and Molecular Biology; James Cerhan, M.D., PhD., Department of Health Science Research


 

Can a form of cellular communication hamstring the newest immunotherapy treatment?

This project will investigate the idea that small particles, called extracellular vesicles, produced by chronic lymphocytic leukemia B cells and secreted into the circulation can bind to chimeric antigen receptor T-cells (CAR T-cells) and blunt their ability to recognize tumor cells. We have identified a specific receptor on the extracellular vesicles as the trigger signal responsible for this impairment of function. This may unveil a unique functional role of leukemic extracellular vesicles. It is also meaningful to see if this mechanism is applicable to other disease states where we know that CAR T-cells also do not work, including solid tumors.

Primary Investigator:  Saad Kenderian, M.B.,Ch.B, Division of  Hematology

Co-investigators:  Neil Kay, M.D., Division of Hematology; Fabrice Lucien-Matteoni, Ph.D., Department of Urology

 


Studying colon cancer to clarify metastasis and identify new treatments

Using patient-derived tumors grown in 3-D vessels (organoids) and artificial intelligence-based approaches we will: Identify potential targets for colon cancer therapy, improve understanding of what causes tumor metastasis, detect patients with tumors at high risk of progression, and identify new treatment methods targeted at slowing or halting tumor progression. We will characterize how a protein associated with epigenetic processes in cells, HP1α, alters cell signaling in colon cancer. We will also characterize how loss of HP1α impacts mitotic fidelity in colon cancer, and we will identify targetable changes in tumor cells caused by disruption of HP1α.

Primary Investigator:  Hu Li, Ph.D., Department of Molecular Pharmacology and Experimental Therapeutics

Co-investigators:  Martin Fernandez-Zapico, M.D., Department of Medical Oncology; Steven Offer, Ph.D., Department of Molecular Pharmacology and Experimental Therapeutics.

 


Obese or not, there’s more to the Type 2 diabetes story

Although obesity is a risk factor for type 2 diabetes mellitus, most people who are obese do not develop diabetes. Their β-cells are able to increase insulin output and maintain normal blood glucose. However, in a subset of people β-cells fail leading to development of the disease. Our group will test whether increased expression of a specific gene/protein (SLC4A4/NBCe1) is the main culprit in leading to failure of β-cells to produce enough insulin in type 2 diabetes mellitus. The ultimate goal of these studies is to provide novel information into how the disease develops, and identify novel therapeutic strategies to treat/prevent this disease.

Primary Investigator:  Aleksey Matveyenko, Ph.D., Department of Physiology and Biomedical Engineering

Co-investigators:  Michael Romero, Ph.D., Department of Physiology and Biomedical Engineering; Taro Hitosugi, Ph.D., Department of Molecular Pharmacology and Experimental Therapeutics.

 


Premature Babies may benefit from more than oxygen

We are testing the hypothesis that prematurity and high oxygen suppress hydrogen sulfide expression and function in the airway, thus blunting the beneficial effects of the gas. We will use cell and mouse models of asthma exposed to moderate hyperoxia and test the efficacy of hydrogen sulfide gas we well as novel hydrogen sulfide donors in inducing bronchodilation and preventing cell proliferation and fibrosis. The results of these novel studies will provide significant insight into the mechanisms of hydrogen sulfide generation and action in developing airways, and conversely the benefit of using the gas as a therapeutic target to treat airway diseases in premature babies.

Primary Investigator:  Christina Pabelick, M.D., Department of Physiology and Biomedical Engineering

Co-investigators:  David Linden, Ph.D., Department of Physiology and Biomedical Engineering; Y.S. Prakash, M.D., Ph.D., Department of Physiology and Biomedical Engineering.

 


 

Lupus, the immune system and Fatty acid processing in the body

The humoral immunity is essential but abnormal B cell activation contributes to autoimmune disorders, including systemic lupus erythematosus, which has no cure and lack new effective treatment. Our preliminary results show that B-cell function relies on fatty acid synthesis mediated by an enzyme, stearoyl-CoA deasaturase. Inhibition of that enzyme alleviates disease pathology in a mouse model of systemic lupus erythematosus. This proposal aims to investigate how stearoyl-CoA deasaturase-mediated fatty acid metabolism modulates B-cell differentiation and autoimmune diseases. We will also examine whether this mechanism is involved in human autoimmune diseases.

Primary Investigator:  Hu Zeng, Ph.D., Division of Rheumatology

Co-investigators:  John Copland III, Ph.D., Department of Cancer Biology; Ian Lanza, Ph.D., Division of Endocrinology, Diabetes, Metabolism, Nutrition; Uma Thanarajasingam, M.D., Ph.D., Division of Rheumatology; Mariam Alexander, M.D., Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology.

More information
Read more about previous CBD awardees on the Center for Biomedical Discovery website.

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Tags: Aleksey Matveyenko, Awards, basic research, CAR-T, Center for Biomedical Discovery, Christina Pabelick, colon cancer, diabetes, Discovery Awards, discovery research, fatty acid metabolism, Hu Li, Hu Zeng, Lupus, News, Paul Galardy, premature babies, Saad Kenderian

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