Monthly Archives: February 2017

OCASCR scientist Lin Liu at work. Photo provided.

Working together, scientists from Oklahoma State University, the University of Oklahoma Health Sciences Center and the Oklahoma Medical Research Foundation are advancing adult stem cell research to treat some of todays most devastating diseases.

Under the umbrella of the Oklahoma Center for Adult Stem Cell Research (OCASCR), created with funding from the Oklahoma Tobacco Settlement Endowment Trust, these scientists have amassed groundbreaking findings in one of the fastest growing areas of medical research.

We have made exciting progress, said OCASCR scientist Lin Liu, director of the Oklahoma Center for Respiratory and Infectious Diseases and director of the Interdisciplinary Program in Regenerative Medicine at Oklahoma State University.

We can convert adult stem cells into lung cells using our engineering process in petri dishes, which offers the possibility to repair damaged lung tissues in lung diseases, said Liu, whose research primarily focuses on lung and respiratory biology and diseases.

Using our engineered cells, we can also reverse some pathological features. These studies give us hope for an eventual application of these cells in humans.

Adult stem cells in the body are capable of renewing themselves and becoming various types of cells.

Until recently, stem cell treatments were largely restricted to blood diseases. However, new studies suggest many other types of adult stem cells can be used for medical treatment, and the Oklahoma Center for Adult Stem Cell Research was created to promote this branch of research.

OCASCR scientist Lin Liu and his team discussing their work. Photo provided.

Liu said the discipline provides hope for many ailments.

What most fascinated me in stem cell research is the hope that we may be able to use stem cells from our own body; for example, bone marrow or fat tissues to cure lung diseases, Liu said.

It is impossible to know exactly which diseases will respond to treatments.However, results of early experiments suggest many diseases should benefit from this type of research, including lung, heart, Alzheimers and Parkinsons diseases, as well as cancer, diabetes and spinal cord injuries. The field is often referred to as regenerative medicine, because of the potential to create good cells in place of bad ones.

While the application of stem cells can be broad, Liu hopes that his TSET-funded work will help develop treatments for diseases caused by tobacco use.

The goal of my research team is to find cures for lung diseases, Liu said. One such disease is chronic obstructive pulmonary disease (COPD).

COPD is the third leading cause of death in the country and cigarette smoking is the leading cause of COPD.

Cigarette smoking is also a risk factor for another fatal lung disease, idiopathic pulmonary fibrosis (IPF), which has a mean life expectancy of 3 to 5 years after diagnosis, he added.

There is no cure for COPD or IPF. The current treatments of COPD and IPF only reduce symptoms or slow the disease progression.

Using OCASCR/TSET funding, my team is researching the possibility to engineer adult stem cells using small RNA molecules existing in the body to cure COPD, IPF and other lung diseases such as pneumonia caused by flu, Liu said.

This is vital research, considering that more than11 million peoplehave been diagnosed with COPD, but millions more may have the disease without even knowing it, according to the American Lung Association.

Despite declining smoking rates and increased smokefree environments, tobacco use continues to cause widespread health challenges and scientists will continue working to develop treatments to deal with the consequences of smoking.

We need to educate the public more regarding the harms of cigarette smoking, Liu said. My research may offer future medicines for lung diseases caused by cigarette smoking.

Under the umbrella of the Oklahoma Center for Adult Stem Cell Research (OCASCR), created with funding from the Oklahoma Tobacco Settlement Endowment Trust, these scientists have amassed groundbreaking findings in one of the fastest growing areas of medical research. Photo provided.

Liu has been conducting research in the field of lung biology and diseases for more than two decades.

However, his interests in adult stem cell therapy began in 2010 when OCASCR was established through a grant with TSET, which provided funding to Oklahoma researchers for stem cell research.

I probably would have never gotten my feet into stem cell research without OCASCR funding support, he said. OCASCR funding also facilitated the establishment of the Interdisciplinary Program in Regenerative Medicine at OSU.

These days, Liu finds himself fully immersed in the exciting world of adult stem cell research and collaborating with some of Oklahomas best scientific minds.

Dr. Liu and his colleagues are really thriving. It was clear seven years ago that regenerative medicine was a hot topic and we already had excellent scientists in the Oklahoma, said Dr. Paul Kincade, founding scientific director of OCASCR. All they needed was some resources to re-direct and support their efforts. OSU investigators are using instruments and research grants supplied by OCASCR to compete with groups worldwide. TSET can point to their achievements with pride.

The Oklahoma Center for Adult Stem Cell Research represents collaboration between scientists all across the state, aiming to promote studies by Oklahoma scientists who are working with stem cells present in adult tissues.

The center opened in 2010 and has enhanced adult stem cell research by providing grant funding for researchers, encouraging recruitment of scientists and providing education to the people of Oklahoma.

We are fortunate that the collaboration at the Oklahoma Center for Adult Stem Cell Research is yielding such positive results, said John Woods, TSET executive director. This research is leading to ground breaking discoveries and attracting new researchers to the field. TSET is proud to fund that investments for Oklahomans.

Funding research is a major focus for TSET and it comes with benefits reaching beyond the lab. For every $1 TSET has invested at OCASCR, scientists have been able to attract an additional $4 for research at Oklahoma institutions, TSET officials said.

TSET also supports medical research conducted by the Stephenson Cancer Center and the Oklahoma Tobacco Research Center.

For more information, visit http://www.ocascr.org.

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OCASCR scientists make progress in TSET-funded adult stem cell research - NewsOK.com

1. A targeted immunoproteasome inhibitor, DPLG3, was found to have high selectivity for the immune cell proteasome and was not toxic to other cell types.

2. When administered after a heart transplant in mice, DPLG3 allowed for minimal graft rejection through a decrease in T cell activation.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Organ transplants typically require the recipient to continue taking immunosuppressive medications to prevent rejection of the graft. However, the toxicity of these medications necessitates a safer option for transplant recipients. Researchers in this study synthesized DPLG3, a molecule that was modeled after a currently prescribed proteasome inhibitor and had selectivity to a subunit of the immunoproteasome.

When tested in vitro, DPLG3 selectively inhibited the 5i immunoproteasome subunit in a lymphoma cell line and did not affect other immunoproteasomes or cell types. The compound was found to decrease T cell proliferation in response to alloantigens. In a mouse model of skin transplantation, treatment with DPLG3 decreased the production of inflammatory cytokines and increased the expression of coinhibitory molecules by T cells. Next, DPLG3 was administered to mice that received a heart transplant from a mouse of another strain. These mice survived longer than the recipients that did not receive the compound, and there were few signs of rejection histologically. In addition, there were fewer effector T cells in the spleen, indicating the inhibition of an immune response. Overall, there was less lymphocyte infiltration and a decrease in T cell activation and proliferation compared to mice not treated with DPLG3. This study demonstrated that the synthesis of a selective proteasome inhibitor to prevent immune response to allografts could potentially allow for a safer and more efficacious medication for transplant recipients.

Click to read the study in PNAS

Relevant Reading: Proteasome inhibition suppresses essential immune functions of human CD4+ T cells

In-Depth [animal study]: An N,C-capped dipeptide, DPLG3, was synthesized to selectively bind to 5i 99,000-fold higher than 5c, a selectivity significantly greater than the currently available proteasome inhibitor. In vitro, DPLG3 inhibited 5i activity in Karpas lymphoma cells, while it had no effect on 5c activity in HepG2 human hepatoma cells. DPLG3 was not cytotoxic to human peripheral blood mononuclear cells. When T cells were isolated from the spleen of mice and treated with increasing concentrations of DPLG3, there was a concentration-dependent decrease in proliferation assessed using 3H-thymidine incorporation (p<0.05). A similar result was seen when mice that received a skin allograft were treated with 25 mg/kg of the compound. Their immune cells showed reduced proliferation in response to alloantigen, increased gene expression of coinhibitory molecules such as CTLA4 and BTLA, as well as a decrease in the pro-inflammatory cytokines IL-2 and IL-17 (p<0.05).

The efficacy of DPLG3 was then tested on C57BL/6 mice that were allografted with hearts from BALB/c mice. The recipient mice were then given 25 mg/kg DPLG3 each day for 14 days after receiving the transplant. These mice were found to have a significant decrease in the percentage of T cells in the spleen (p<0.05), demonstrating a lack of immune activation. In addition, the splenocytes demonstrated reduced responsiveness to alloimmune stimuli and there was a significant decrease in histologic signs of graft rejection. The treated mice had overall longer graft survival, with no death seen with 2 weeks of treatment with DPLG3 and a single dose of 25 g CTLA4 Ig.

Image: PD

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This text summarizes the key trials in:General Medicine and Chronic Disease, Cardiology, Critical and Emergent Care, Endocrinology, Gastroenterology, Hematology and Oncology, Imaging, Infectious Disease, Nephrology, Neurology, Pediatrics, Psychiatry, Pulmonology, and Surgery.

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Inhibition of the immunoproteasome may improve graft acceptance [PreClinical] - 2 Minute Medicine