Research on 3D scaffolds sets new bar in lung regeneration

In end-stage lung disease, transplantation is sometimes the only viable therapeutic option, but organ availability is limited and rejection presents an additional challenge. Innovative research efforts in the field of tissue regeneration, including pioneering discoveries by University of Vermont Professor of Medicine Daniel Weiss, M.D., Ph.D., and colleagues, hold promise for this population, which includes an estimated 12.7 million people with chronic obstructive pulmonary disorder (COPD), the third leading cause of death in the U.S.In the past year alone, Weiss and colleagues published four articles in Biomaterials, the leading bioengineering journal, as well as two March 2014 articles by first author Darcy Wagner, Ph.D., a postdoctoral fellow working in Weiss’ lab, reporting their development of new methods and techniques for engineering lungs for patients with COPD and pulmonary fibrosis.Weiss and his team’s work focuses on lung tissue bioengineering, which involves the use of a scaffold — or framework — of lungs from human cadavers to engineer new lungs for patients with end-stage disease. Their studies have examined multiple perspectives on the process of stripping the cellular material from these lungs — called decellularizing — and replacing it with stem cells (recellularization), in an effort to grow new, healthy lungs for transplantation.Working in animal and human models, Wagner, Weiss and colleagues have addressed numerous challenges faced during the lung tissue bioengineering process, such as the storage and sterilization of decellularized cadaveric scaffolds and the impact of the age and disease state of donor lungs on these processes.In one of the latest Biomaterials studies, the researchers report on novel techniques that increase the ability to perform high-throughput studies of human lungs.”It’s expensive and difficult to repopulate an entire human lung at one time, and, unlike in mouse models, this doesn’t readily allow the study of multiple conditions, such as cell types, growth factors, and environmental influences like mechanical stretch — normal breathing motions — that will all affect successful lung recellularization,” explains Weiss.To address this, Wagner developed a technique to dissect out and recellularize multiple, small segments in a biological/physiological manner that would take into consideration the appropriate three-dimensional interaction of blood vessels with the lung’s airways and air sacs.Working with biomaterials scientist Rachel Oldinski, Ph.D., UVM assistant professor of engineering, they further developed a new method using a nontoxic, natural polymer derived from seaweed to use as a coating for each lung segment prior to recellularization. This process allowed the team to selectively inject new stem cells into the small decellularized lung segments while preserving vascular and airway channels. Use of this technique, which resulted in a higher retention of human stem cells in both porcine (pig) and human scaffolds, allows the small lung segments to be ventilated for use in the study of stretch effects on stem cell differentiation.”The ability to perform numerous experiments and screen multiple conditions from a single decellularized human lung provides an avenue to accelerate progress towards the eventual goal of regenerating functional lung tissue for transplantation,” says Wagner.Through another novel technique — thermography or thermal imaging — Wagner and colleagues developed a non-invasive and non-destructive means for monitoring the lung scaffolds’ integrity and physiologic attributes in real-time during the decellularization process. According to Wagner, this method could be used as a first step in evaluating whether the lungs and eventual scaffolds are suitable for recellularization and transplantation.The development of these new techniques are “a significant step forward” in the field of lung regeneration, say Wagner and her coauthors.This study and Weiss’ and Wagner’s related publications over the past 15 months showcase the positive impact of the $4.26 million National Institutes of Health (NIH) Director’s Opportunity for Research grant Weiss received in October 2010 as part of the American Recovery and Reinvestment Act funding. In addition to these scientific accomplishments, he’s forged strong industry ties, as well, and has several patents pending.”This work serves as a core for helping develop a robust bioengineering effort to parallel ongoing stem cell activities in the Department of Medicine and for fostering increasing collaborative efforts between the Colleges of Medicine and Engineering,” says Weiss.Story Source:The above story is based on materials provided by University of Vermont. Note: Materials may be edited for content and length.

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New approach to prevent diabetes-induced birth defects?

Aug. 28, 2013 — A research team at the University of Maryland School of Medicine has identified a cell signaling pathway which plays a significant role in causing developmental defects of the fetal spinal cord and brain in babies of women with diabetes. Using an animal model of disease, the team’s results point to a potential new therapeutic target for preventing these defects in pregnant women having preexisting diabetes.The results of this study are published in the August 27th issue of Science Signaling.”Providing the best possible care for women before and during early pregnancy is a significant challenge because the first trimester is such a crucial time of development, and many women may not be aware that they are pregnant,” says Dean E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers distinguished professor and dean of the School of Medicine. “Prenatal care is especially important for women who have diabetes because research has shown that even transient increases in blood glucose can lead to serious, and sometimes life-threatening, birth defects.”According to the U.S. Centers for Disease Control and Prevention, approximately 1 in 33 babies in the United States are born with a birth defect. Neural tube defects (NTDs), which occur when the fetal spinal column does not close completely in the first trimester, are among the most common type of birth defects and affect about 3,000 pregnancies each year. Women with diabetes prior to pregnancy are 3- to 10-times more likely to have a child with NTDs than women without disease. …

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Tumor suppressor may actually fuel aggressive leukemia

Aug. 27, 2013 — New research in the Journal of Clinical Investigation suggests that blocking a protein normally credited with suppressing leukemia may be a promising therapeutic strategy for an aggressive form of the disease called acute myeloid leukemia (AML).Researchers from Cincinnati Children’s Hospital Medical Center report their results in a study posted online Aug. 27 by the journal.The protein scientists targeted is a transcription factor known as RUNX1, which also plays an important role in helping regulate the normal development of blood cells. The researchers were surprised to discover in their laboratory tests that RUNX1 was supporting the growth of AML fueled by what are called fusion proteins.”RUNX1 is generally considered a tumor suppressor in myeloid neoplasms, but our study found that inhibiting its activity rather than enhancing it could be a promising therapeutic strategy for AMLs driven by fusion proteins,” said James Mulloy PhD., a researcher in the Division of Experimental Hematology and Cancer Biology at Cincinnati Children’s and lead investigator.AML develops and progresses rapidly in patients, requiring prompt treatment with chemotherapy, radiation or bone marrow transplant. These treatments can be risky or only partially effective depending on the patient as well as the variation and progression of disease. Researchers like Mulloy are searching for improved treatment strategies, including targeted molecular approaches that could potentially be more effective and carry fewer side effects.They tested this finding in a genetic mouse model of AML developed by Mulloy’s laboratory that is driven by fusion proteins and a mixed-lineage leukemic gene called MLL-AF9. The researchers genetically inhibited both RUNX1 and an associated protein called core-binding factor subunit beta (Cbfb). By doing so, the researchers were able to stop the development of leukemia cells, demonstrating the potential viability of RUNX1 as a therapeutic target.Also collaborating on the research was Paul Liu, MD, PhD, at the National Cancer Institute (National Institutes of Health), who developed a small molecule that specifically inhibits RUNX1. Using this inhibitor, the researchers showed that the AML cells were more sensitive than normal blood cells, indicating the inhibitor may be useful in the future as a therapy for patients with AML.The research team continues to test inhibition of RUNX1 in AMLs driven by fusion proteins and in other blood disorders involving RUNX1. Their goal is to see how their findings might eventually lead to potential treatment of human disease.Funding support for the research came, in part, from the National Institutes of Health’s National Center for Research Resources (1UL1RR026314-01), a U.S. …

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Long-sought method to efficiently make complex anticancer compound developed

Aug. 1, 2013 — Scientists at The Scripps Research Institute (TSRI) have achieved the first efficient chemical synthesis of ingenol, a highly complex, plant-derived compound that has long been of interest to drug developers for its anticancer potential. The achievement will enable scientists to synthesize a wide variety of ingenol derivatives and investigate their therapeutic properties. The achievement also sets the stage for the efficient commercial production of ingenol mebutate, a treatment for actinic keratosis (a common precursor to non-melanoma skin cancer), that at present must be extracted and refined inefficiently from plants.”I think that most organic chemists had considered ingenol beyond the reach of scalable chemical synthesis,” said TSRI Professor Phil S. Baran.Baran and his laboratory report their achievement in this week’s issue of Science Express, the early online edition of the journal Science.An Anticancer Substance from NatureIngenol and its derivatives are found in the widely distributed Euphorbia genus of plant, whose milky sap has long been used in traditional medicine to treat skin lesions. Ingenol mebutate, extracted from the common “petty spurge” plant (E. peplus), was recently approved by the U.S. FDA, European Medicines Agency, Medicines Australia and Health Canada to treat actinic keratosis, a common type of precancerous lesion associated with cumulative sun exposure. Formulated and marketed as Picato®, the drug has also shown effects in models and in early trials of non-melanoma skin cancers.In late 2011, the drug’s manufacturer, Denmark-based LEO Pharma, collaborated with Baran’s laboratory to find an efficient way to synthesize ingenol mebutate using organic chemistry — the usual method for producing modern drugs. “At the time, the only way to get the product was by a relatively lengthy extraction process from the E. …

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New drug targets for aggressive breast cancer

July 26, 2013 — Scientists at A*STAR’s Genome Institute of Singapore (GIS) led in a study that has identified genes that are potential targets for therapeutic drugs against aggressive breast cancer. These findings were reported in the July 2013 issue of PNAS.Out of the 1.5 million women diagnosed with breast cancer in the world annually, nearly one in seven of these is classified as triple negative. Patients with triple-negative breast cancer (TNBC) have tumours that are missing three important proteins that are found in other types of breast cancer. The absence of these three proteins make TNBC patients succumb to a higher rate of relapse following treatment and have lower overall survival rates. There is currently no effective therapy for TNBC.Using integrated genomic approaches, GIS scientists led by Dr. Qiang Yu, in collaboration with local and international institutions, set out to search for targets that can be affected by drugs. The scientists discovered that a protein tyrosine phosphatase[1], called UBASH3B, is overexpressed in one third of TNBC patients. UBASH3B controls the activity of an important breast cancer gene. The researchers found that deleting this gene expression markedly inhibits TNBC cell invasive growth and lung metastasis in a mouse model. They also showed that patients with TNBC tumours that have high levels of UBASH3B tend to be more likely to have early recurrence and metastasis.Lead author Dr Qiang Yu said, “The identification of target genes is always the most crucial first step towards treating a disease. …

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Protein responsible for ‘bad’ blood vessel growth discovered

July 17, 2013 — The discovery of a protein that encourages blood vessel growth, and especially ‘bad’ blood vessels – the kind that characterise diseases as diverse as cancer, age-related macular degeneration and rheumatoid arthritis – has been reported in the journal Nature.The team at the UCL Institute of Ophthalmology discovered the new protein, called LRG1, by screening for mouse genes that are over-expressed in abnormal retinal blood vessels in diseased eyes.In these diseased retinas the LRG1 protein is expressed by blood vessel endothelial cells, which line blood vessel walls. LRG1 is also present in the eyes of patients with proliferative diabetic retinopathy – a vascular complication of diabetes that can lead to blindness.The study shows that, in mouse models, LRG1 promotes the growth of blood vessels in a process known as ‘angiogenesis’. Conversely, inhibition of LRG1 in mouse models reduces the harmful blood vessel growth associated with retinal disease.The authors of the study suggest that blocking LRG1’s activity is a promising target for future therapy.Professor John Greenwood, senior author of the research from the UCL Institute of Ophthalmology said: “We have discovered that a secreted protein, LRG1, promotes new blood vessel growth and its inhibition prevents pathological blood vessel growth in ocular disease.”Our findings suggest that LRG1 has less of a role in normal blood vessel growth and so may be particularly applicable to ‘bad’ blood vessel growth. This makes LRG1 an especially attractive target for therapeutic intervention in conditions where vessel growth contributes to disease.”Angiogenesis is an essential biological process that is required for development, reproduction and the repair of damaged tissues. However angiogenesis also plays a major role in many diseases where new vessel growth can be harmful.For example, in the retina uncontrolled and irregular blood vessel growth in diseases such as age-related macular degeneration and diabetic retinopathy can result in a catastrophic loss of vision. Another example is the growth of cancerous solid tumours, which are dependent on the proliferation of new blood vessels. Angiogenesis is also an important feature of rheumatoid arthritis, where it contributes to the inflammation of the joint.In previous studies, many signaling molecules have been identified that control angiogenesis, with the secreted protein vascular endothelial growth factor (VEGF) being considered as the master regulator. Therapeutic targeting of VEGF has resulted in improved outcomes in eye diseases with vascular complications and in some cancers but it is clear that additional therapeutic targets need to be identified.The mechanism through which LRG1 promotes angiogenesis is by modifying the signalling of a multifunctional secreted growth factor called transforming growth factor beta (TGF-beta). TGF-beta regulates both the maintenance of normal healthy blood vessels, and the unwanted growth of harmful blood vessels, but precisely how it promotes two opposing outcomes is a biological paradox.This study indicates that in the retinal diseases investigated LRG1 production is ‘turned on’ in blood vessels. This causes a switch in TGF-beta signalling away from a normal vessel maintenance pathway towards a pathway that promotes the growth of new harmful blood vessels.Professor Stephen Moss, senior author from the UCL Institute of Ophthalmology said: “Genetic studies have revealed that the gene that codes for LRG1 is conserved in vertebrates, and this study confirms that mouse and human blood vessels express LRG1.”We predict, therefore, that abnormal blood vessel growth is also a conserved process and that the role of LRG1 is equally applicable to human pathological angiogenesis.”He added: “Work is already underway to develop a therapeutic antibody that targets LRG1.”

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A new model — and possible treatment — for staph bone infections

June 19, 2013 — Osteomyelitis — a debilitating bone infection most frequently caused by Staphylococcus aureus (“staph”) bacteria — is particularly challenging to treat.Now, Vanderbilt microbiologist Eric Skaar, Ph.D., MPH, and colleagues have identified a staph-killing compound that may be an effective treatment for osteomyelitis, and they have developed a new mouse model that will be useful for testing this compound and for generating additional therapeutic strategies.James Cassat, M.D., Ph.D., a fellow in Pediatric Infectious Diseases who is interested in improving treatments for children with bone infections, led the mouse model studies. Working with colleagues in the Vanderbilt Center for Bone Biology and the Vanderbilt University Institute of Imaging Science, Cassat developed micro-computed tomography (micro-CT) imaging technologies to visualize a surgically introduced bone infection in progress.”The micro-CT gives excellent resolution images of the damage that’s being done to the bone,” said Skaar, the Ernest W. Goodpasture Professor of Pathology. “We found that staph is not only destroying bone, but it’s also promoting new bone growth. Staph is causing profound changes in bone remodeling.”Cassat also established methods for recovering — and counting — bacteria from the infected bone.”We’re not aware of any other bone infection models where you can pull the bacteria out of a bone and count them in a highly reproducible manner,” Skaar said. “From a therapeutic development standpoint, we think this model is going to allow investigators to test new compounds for efficacy against bone infections caused by staph or any other bacteria that cause osteomyelitis.”Several pharmaceutical companies have already approached Skaar and his team about testing compounds in the new bone infection model, which the investigators describe in the June 12 issue of Cell Host & Microbe.Using the model, the team demonstrated that a certain protein secreted by staph plays a critical role in the pathogenesis of osteomyelitis. Understanding the specific bacterial factors — and the bone cell signals — that promote bone destruction and formation during infection could lead to new strategies for restoring bone balance, Skaar said.”Even if it’s not possible to kill the bacteria, compounds that manipulate bone growth or destruction might have some therapeutic benefit.”Still, Skaar is interested in treatments that will eliminate the infection.The staph bacteria involved in osteomyelitis and in other persistent infections (such as lung infections in cystic fibrosis) are often a sub-class of staph known as “small colony variants.” These staph variants grow slowly and are resistant to entire classes of antibiotics commonly used to treat bone and lung infections, Skaar said.One way that staph bacteria become antibiotic-resistant small colony variants is by changing the way they generate energy. Instead of using respiration, they switch to fermentation, which blocks antibiotic entry and slows bacterial growth.In a high-throughput screen for compounds that activate a heme-sensing bacterial pathway, graduate student Laura Mike identified a compound that kills fermenting staph. The findings are reported in the May 14 issue of the Proceedings of the National Academy of Sciences.”This is a completely new molecular activity,” Skaar said. “We don’t know of other molecules that are toxic against fermenting bacteria.”The compound — and derivatives synthesized by Gary Sulikowski, Ph.D., and his team — might be useful in treating staph small colony variants, or in preventing their emergence.The investigators demonstrated in culture that treating staph with the antibiotic gentamicin forced it to become a small colony variant and ferment, and that co-treatment with the new compound prevented resistance and killed all of the bacteria.”We think a really interesting therapeutic strategy for this compound is that it might augment the antimicrobial activity of existing classes of antibiotics by preventing resistance to them — it might extend the lifetime of these classes of antibiotics,” Skaar said.This would be similar to the drug Augmentin, which combines a traditional penicillin-type antibiotic and a compound that blocks bacterial resistance.The investigators are excited to test the new compound in the mouse model of osteomyelitis. …

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Chemical nanoengineering: Designing drugs controlled by light

June 18, 2013 — The scientific cooperation between chemists, biotechnologists and physicists from various Catalan institutes, headed by Pau Gorostiza, from the Institute for Bioengineering of Catalonia (IBEC), and Ernest Giralt, from the Institute for Research in Biomedicine (IRB Barcelona), has led to a breakthrough that will favor the development of light-regulated therapeutic molecules.The “Design, synthesis and structure of peptides and proteins” lab headed by Dr. Giralt, also senior professor at the University of Barcelona and holder of the 2011 Spanish National Research Prize, has synthesized two peptides (small proteins), which, on irradiation with light, change shape, thereby allowing or preventing an specific protein-protein interaction. The association of these two proteins is required for endocytosis, a process by which cells allow molecules to cross the cell membrane and enter. The Italian scientist Laura Nevola, postdoctoral researcher who works in Dr. Giralt’s lab, and Andrés Martín-Quirós, a PhD student with Dr. Gorostiza’s lab, co-authors of the study, have spent four years working on the design of photo-sensitive peptides.”Photo-sensitive peptides act like traffic lights and can be made to give a green or red light for cell endocytosis. They are powerful tools for cell biology,” explains Dr. Giralt. “These molecules allow us to use focalized light like a magic wand to control biological processes and to study them,” adds the physicist Pau Gorostiza, ICREA professor, and head of the “Nanoprobes and nanoswitches” lab at IBEC.The researchers highlight the immediate applicability of these molecules to study, for example, in vitro endocytosis in cancer cells -where this process is uncontrolled- which would allow selective inhibition of the proliferation of these cells. Also, they would also allow the study of developmental biology -where cells require endocytosis to change shape and function, processes that are orchestrated with great spatial and temporal precision. …

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New way to clear cholesterol from the blood

Apr. 10, 2013 — Researchers at the University of Michigan have identified a new potential therapeutic target for lowering cholesterol that could be an alternative or complementary therapy to statins.

Scientists in the lab of David Ginsburg at the Life Sciences Institute inhibited the action of a gene responsible for transporting a protein that interferes with the ability of the liver to remove cholesterol from the blood in mice. Trapping the destructive protein where it couldn’t harm receptors responsible for removing cholesterol preserved the liver cells’ capacity to clear plasma cholesterol from the blood, but did not appear to otherwise affect the health of the mice.

In the research, published April 9 in the online journal eLife, scientists found that mice with an inactive SEC24A gene could develop normally. However, their plasma cholesterol levels were reduced by 45 percent because vesicles from liver cells were not able to recruit and transport a critical regulator of blood cholesterol levels called proprotein convertase subtilisin/kexin type 9. PCSK9 is a secretory protein that destroys the liver cells’ receptors of low-density lipoprotein- LDL, the so-called “bad cholesterol” — and prevents the cells from removing the LDL.

“Inhibiting SEC24A or PCSK9 may be an alternative to statins, and could work together with statins to produce even greater effects,” said Xiao-Wei Chen of the Ginsburg lab, the first author on the paper. “Also, they might be effective on patients who are resistant to or intolerant of statins.”

Initial studies of anti-PCSK9 therapies in humans have shown that eliminating PCSK9 can lower cholesterol dramatically and work with statins like Lipitor to lower it even further. The Ginsburg lab’s research points to a new area for study: rather than inhibiting PCSK9 itself, perhaps future therapies could block the transport mechanism that allows the destructive protein to reach the LDL receptors.

The paper, “SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion,” explains the mechanism by which cells transport PCSK9. Vesicles transport proteins in the cell; the Ginsburg lab’s research focused on a specialized type of vesicle packaged by the Coat Protein Complex II, which regulates the metabolism of cholesterol, among many other things. These vesicles selectively transport cargo proteins including PCSK9.

Without those LDL receptors (LDLR), liver cells are not able to remove LDLs from the bloodstream, so protecting the LDLR from PCSK9 would allow the receptors to continue to remove cholesterol.

“Without SEC24A, much of the PCSK9 couldn’t make its way out of the cells to destroy the LDLR, which then clears cholesterol from the blood,” Chen said.

The part of the vesicle that selects which proteins to transport is SEC24. By blocking SEC24A gene, the researchers disabled the vesicle’s selection of PCSK9. The destructive protein remained trapped within the cells, leaving the LDLR intact and enabling the liver to clear the body of cholesterol that otherwise could accumulate in arteries.

“We have no reason at this point to expect that this strategy will be any better than anti-PCSK9 therapy for treating high cholesterol, but it would be another alternative approach, and it’s hard to predict which drugs will work the best and be the safest until we actually try them out in people,” Ginsburg said.

Ginsburg is a research professor at the Life Sciences Institute, where his laboratory is located. He is also the James V. Neel Distinguished University Professor and the Warner-Lambert/Parke-Davis Professor in the Division of Molecular Medicine and Genetics, Department of Internal Medicine and departments of Human Genetics and Pediatrics at the U-M Medical School and a Howard Hughes Medical Institute Investigator.

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