Cincinnati Children’s joins tissue chip project

Cincinnati Children's joins tissue chip project.A scientist at Cincinnati Children’s is one of 17 investigators nationwide to receive a grant from a $13 million research fund to develop human tissue chips for drug screening purposes.

The goal is to develop 3-D human tissue models that accurately mimic the structure and function of human organs. Once developed, tissue chips will help researchers better predict drug safety in human clinical trials.

James Wells, PhD, a researcher in the Division of Developmental Biology, will focus on generating human intestinal organoids with a functioning enteric nervous system. This version of a tissue chip would allow studies of prospective drugs to treat gastrointestinal motility disorders, which affect up to 25 percent of the US population.

Wells’ project is an outgrowth of a breakthrough study, published online in December 2010 in the journal Nature, which reported success in creating functioning human intestinal tissue from pluripotent stem cells.

The national tissue chip project is funded by the National Institutes of Health (NIH) in collaboration with the Defense Advanced Research Projects Agency (DARPA) and the US Food and Drug Administration. The project is the first collaboration to be launched by the NIH’s newly created center, the National Center for Advancing Translational Sciences (NCATS).

New program to focus on mitochondrial disease

Taosheng Huang, MD, PhD.Taosheng Huang, MD, PhD, a geneticist from the University of California Irvine, will direct the new Mitochondrial Disease Program at Cincinnati Children’s. The program, based in the Division of Human Genetics, will integrate basic and translational research, clinical care and genetic testing to improve care for children with mitochondrial diseases.

Mitochondria play a critical role in many fundamental cellular functions and are the “powerhouses” of cells, which produce over 90 percent of the energy required by a cell. Mitochondria also generate reactive oxygen species (ROS) and participate in apoptosis, aging and other important cellular functions. Dysfunction of mitochondria can affect almost every cell and organ system and has been implicated in a wide range of diseases, such as Kearns- Sayre syndrome, Leigh syndrome, hearing loss and vision impairment, cancer and diabetes. Clinically this group of diseases can present with poor growth, loss of coordination, muscle weakness, developmental delay and other neurological problems.

Huang earned his medical degree and a master’s degree in biochemistry in China and went on to receive a PhD in Biomedical Science from the Mount Sinai Medical School in New York. He completed his pediatric residency at Georgetown University Medical Center and his fellowship in clinical genetics and clinical molecular genetics at Harvard Medical School before coming to Cincinnati Children’s. Huang served as the director of the MitoMed diagnostic laboratory and in several clinical and research roles at the University of California Irvine since 1991.

Huang will continue his research using “next-gen” sequencing to identify disease-causing genes. He will continue work to develop an induced pluripotent stem cell (iPSC) therapy to treat optic atrophy and other mitochondrial diseases. And he will help diagnose and treat children with these diseases.

Grant expands blood vessel research

Dr. Richard Lang.Findings have implications for macular degeneration and cancer tumor growth

A $1.9 million grant will support work at Cincinnati Children’s to explore how a cellular “policeman” controls the way blood vessels form new branches. The five-year grant from the National Eye Institute will allow researchers to expand their findings.

In 2011, research led by Richard Lang, PhD, Director of the Visual Systems Group at Cincinnati Children’s, revealed a new molecular pathway used to suppress blood vessel branching in the developing retina. The findings, published in Nature, could lead to new ways to treat retinal diseases and slow tumor growth in a variety of cancers.

The research focuses on the role myeloid cells – known as the “policemen of multicellular organisms” – play in determining how frequently blood vessels form new branches. Studying eye development in mice, Lang’s research team reported that myeloid cells use the Wnt-Flt1 pathway to regulate vascular branching.

Ramping up the expression of Flt1 slows down branching, which could be useful in fighting cancer tumors and eye diseases such as retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. Turning down the process stimulates branching, which could help treat blindness related to inactive retinas and speed repair of other damaged tissues.

The research was made possible by developing a mouse model that deletes targeted genes only in the retina, Lang says. If those genes were deleted elsewhere in the body, the developing mouse would not survive to reach birth.

Network will merge genetic data, electronic medical records

Dr. John Harley.A $2.4 million federal grant connects Cincinnati Children’s to a national effort to build massive patient databases to advance research in autism, cardiac disease, early childhood obesity and other health conditions.

John Harley, MD, PhD, Director, Division of Rheumatology at Cincinnati Children’s, is principal investigator for the grant, which was recently awarded by the National Human Genome Institute (NHGI). The project will merge clinical data gathered by electronic patient records with a rapidly expanding pool of genetic and molecular research data about disease.

“In some studies, we can obtain meaningful results with as few as 100 subjects,” Harley says. “But other studies may require 30,000 subjects or more. It takes a large network to gather such enormous quantities of data.”

NHGI created the Electronic Medical Records and Genomics (eMERGE) Network in September 2007. Phase I work, which ended in 2011, primarily involved adult medical centers. Phase II, to run through July 2015, adds three pediatric medical centers to the now 10-center network: the Children’s Hospital of Philadelphia; and Cincinnati Children’s and Boston Children’s Hospital.

Phase II will incorporate genetic data into electronic medical records to use in genetic risk assessment, disease prevention, diagnosis and treatment. The network also will study ways to address consent, education, regulation and consultation issues, the NHGI states.

Harley says the data network could slash the costs of conducting genome-wide association studies as much as 90 percent.

Davies honored as EL AM fellow

Stella Davies, MBBS, PhD, MRCP.Physician is Cincinnati Children's 11th participant

Stella Davies, MBBS, PhD, MRCP, Director of the Division of Bone Marrow Transplantation and Immune Deficiency, has been appointed Cincinnati Children’s eleventh Executive Leadership in Academic Medicine (ELAM) fellow.

Davies will join a group of 54 other women in medicine, science and dentistry from around the country in this year’s ELAM class. The program began at Drexel University in 1995 to help build leadership skills and connections among women in medicine and the sciences.

Davies’ medical and scientific career spans a quarter of a century, with the past 10 years spent at Cincinnati Children’s. Her daily work with some of the sickest children is something that she says drives her every day.

“There have been enormous changes in what we can offer these children, “ she says. “When I first started, children diagnosed with leukemia had no hope for survival. Now they have a 75 percent chance of cure. That’s the change we’ve seen.”

As an ELAM participant, Davies will attend several weeks of class sessions during the year and will complete a leadership project at Cincinnati Children’s.

“It’s an opportunity to meet and network with women in other disciplines, with different lives,” Davies says. “It’s something that will help me grow."

Drug Shows Promise in Halting Cancer Growth

Dr. Yi Zheng.Early findings also show potential for nerve cell repair

Scientists at Cincinnati Children’s have developed a small-molecule-inhibiting drug that in early laboratory tests stopped breast cancer cells from spreading and promoted the growth of early nerve cells.

Researchers reported their findings online June 21 in Chemistry & Biology. They named their lead drug candidate “Rhosin.” The inhibitor targets a single component of a cell signaling protein complex called Rho GTPases, which regulate cell movement and growth throughout the body. Miscues in Rho GTPase processes are widely implicated in human diseases, including cancers and neurologic disorders.

“Rhosin could be useful in therapy for many kinds of cancer or possibly neuron and spinal cord regeneration,” says Yi Zheng, PhD, lead investigator and Director of Experimental Hematology and Cancer Biology. He cautions that the drug is still years from use in humans.

“We’ve performed in silica (computerized) rational drug design, pharmacological characterization and cell tests in the laboratory, and are now starting to work with mouse models.”

In the published study, Zheng and colleagues started with the extensive body of research into the processes and functions of Rho GTPases, then used high-throughput computerized molecular screening and computerized drug design to reveal a druggable target site. Once they confirmed the targeting and binding capabilities of Rhosin to RhoA, the researchers tested the candidate drug’s impact on cultured breast cancer cells and nerve cells.

Rhosin inhibited cell growth and the formation of mammary spheres, acting specifically on RhoA molecular targets without disrupting other critical cellular processes. Rhosin did not affect noncancerous breast cells.

Researchers also treated neuronal cells with Rhosin and nerve growth factor. The combination promoted the proliferation of branching neurites – developing nerve cells - from the neuronal cells.

‘Herd’ effect works on HPV

Vaccinating teens with human papillomavirus vaccine (HPV) has had the unexpected benefit of decreasing HPV infection even in teens not immunized.

Results of the NIH-funded study led by Jessica Kahn, MD, MPH, Division of Adolescent Medicine at Cincinnati Children’s, were published July 9 in the online version of Pediatrics. It is the first study to show a substantial decrease in HPV infection in a community as well as herd protection – a decrease in infection rates among non-immunized individuals that occurs when a critical mass of people in a community is immunized against a contagious disease.

The study involved 409 sexually experienced young women between the ages of 13 and 16 from two primary care clinics in the city of Cincinnati. More than half of the girls had received at least one dose of the HPV vaccine. The researchers compared pre- and post-vaccination HPV prevalence rates; the prevalence of vaccine-type HPV decreased 58 percent overall, from 31.7 percent to 13.4 percent. The decrease was high among vaccinated participants (69 percent), but also was substantial for those who were unvaccinated (49 percent).

“The results are promising in that they suggest that vaccine could substantially reduce rates of cervical cancer in this community in the future,” Kahn says.

Despite the evidence of herd immunity, Kahn emphasizes that vaccination of all young women between the ages of 11 and 26 is important to reduce rates of HPV infection, which ultimately can lead to cervical cancer.

She adds that larger studies with more representative samples are needed to definitively determine the public health impact of the HPV vaccine.

Rejuvenating Aging Stem Cells

Dr. Hartmut Geiger.Study shows promise for illnesses of aging

Researchers have rejuvenated aged hematopoietic stem cells, offering intriguing clues into how medicine might one day fend off some ailments of old age.

Scientists at Cincinnati Children’s Hospital Medical Center and the University of Ulm School of Medicine in Germany reported their findings online May 3 in Cell Stem Cell. The discovery challenges the belief that the aging of hematopoietic stem cells (HSCs) was locked in by nature and not reversible.

HSCs originate in the bone marrow and generate the body’s red and white blood cells and platelets. They are essential to the immune system. As we age, HSCs become more numerous but less effective at regenerating cells. This makes older people more susceptible to infections and disease, including leukemia.

Study researchers determined that a protein that regulates cell signaling – Cdc42 – also controls a molecular process that causes HSCs in mice to age. Pharmacologic inhibition of Cdc42 reversed HSC aging and restored function to that of younger stem cells.

“Our findings identify the activity of Cdc42 as a target for ameliorating natural HSC aging,” says Hartmut Geiger, PhD, the study’s principal investigator. “We know the aging of HSCs reduces the immune system response in older people, which contributes to diseases such as anemia and may be the cause of tissue attrition in certain systems of the body.”

The findings are early and confined to mouse studies, so it remains to be seen what application they may have for humans. Still, the study expands what is known about the basic molecular and cellular mechanisms of aging.

Protein Protects Organs During Severe Illness

Protein protects organs during severe illness.A protein that protects cells during injury could eventually translate into treatment for conditions ranging from cardiovascular disease to Alzheimer’s.

Reported online June 7 in the journal Cell, researchers showed that the protein thrombospondin activates a protective pathway that prevents heart cell damage in mice undergoing simulated hypertension, cardiac pressure overload and heart attack.

“Our results suggest that this protein could be targeted medically as a way to help people with disease states where various organs are under stress,’’ says Jeffery Molkentin, PhD, lead investigator and researcher in the Heart Institute at Cincinnati Children’s and the Howard Hughes Medical Institute. Molkentin added that although further study is needed, potential clinical application could include drug or gene therapy to increase expression of the protein in tissues or organs undergoing injury.

Thrombospondin (Thbs) proteins are produced in cells where tissues are being altered or injured, such as in chronic cardiac disease. Thbs triggers a process that helps correct or rid cells of proteins that misfold. Misfolded proteins can cause tissue damage and organ dysfunction.

The researchers focused on how the thrombospondin protein Thbs4 activates cellular stress responses in mice bred to overexpress the protein in heart cells. Scientists compared the response of Thbs4-positive mice to those not bred to overexpress the protein.

During simulated hypertension and cardiac infarction, the protein reduced injury and protected the Thbs4-positive mice from death. The mice not bred for Thbs4 overexpression were extremely sensitive to cardiac injury, says Molkentin.

Funding support for the study came from the National Institutes of Health and the Howard Hughes Medical Institute.

New law affects physician training, genetic counselors

Dr. Arnold Strauss.A new law in Ohio will make it easier for visiting international physicians to receive hands-on training at Cincinnati Children’s.

The same law also requires that genetic counselors in the state are licensed.

On June 6, Ohio Gov. John Kasich signed a bill that creates a Visiting Clinical Professional Development Certificate, allowing non-US physicians to work with patients for up to one year under close supervision by a US physician. Only nine other US states and territories have similar rules.

Visiting doctors may take medical histories, conduct physical examinations, perform surgery, administer anesthesia and conduct radiologic studies. Previously, they could only observe such procedures.

Cincinnati Children’s has more than 170 non-US physicians participating in observership programs. Visitors will be practicing under the new rules by mid-2013, says Julie Morin, MHSA, regional manager for International Business Development at Cincinnati Children’s Global Health Center.

Cincinnati Children’s also supported a law that requires genetic counselors in Ohio to be licensed.

The change helps assure that experts meet a high set of professional standards before they provide interpretation and education to families about the results of genetic testing, says Melanie Myers, PhD, MS, CGC, Director of the Genetic Counseling Graduate Program at Cincinnati Children’s.

“We are seeing a rise in direct-to-consumer genetic testing,” Myers says. “With more people purchasing at-home test kits, it becomes extremely important that they have access to a qualified genetic counselor to help them understand the results, their risks and their options.”