Flipping The Switch On Aging
Dr. Hartmut Geiger has identified a protein that appears to accelerate the aging process.
Researchers here and at the Ulm University Medicine in Germany have found a molecular switch that could be a key to slowing the ravages of aging.
Published online in October in Nature, the study builds on the team’s 2012 findings that they could rejuvenate aging hematopoietic stem cells (HSCs) in laboratory mice. HSCs originate in the bone marrow and generate all of the body’s red and white blood cells and platelets.
Although it is well established that HSCs become less effective as we age, scientists do not understand how this happens. “This study puts us significantly closer to that goal through novel findings that show a distinct switch in a molecular pathway is critical to the aging process,” says Hartmut Geiger, PhD, the study’s senior investigator.
The pathway Geiger refers to is the Wnt signaling pathway, which regulates communications and interactions between cells in animals and people. Geiger and his team observed in animal studies that the protein Wnt5a disrupted normal Wnt signaling patterns in aging cells. When the scientists increased Wnt5 in young HSCs, the increase activated the protein Cdc42 and the cells began to age. Cdc42 is the same protein the scientists targeted in their 2012 study, in which they showed that inhibiting Cdc42 reversed the aging process and rejuvenated HSCs.
In this current study, the researchers deleted Wnt5a from the HSCs of mice, thereby rejuvenating the HSCs and delaying the aging process in blood-forming stem cells.
The authors emphasized the need for more research before the findings become therapeutically relevant to people. They hope their work will lead to strategies that will help the elderly boost their immune systems, fight illnesses and enhance overall vitality.
$9.1M Grant Targets Sickle Cell-Related Organ Damage
Dr. Punam Malik will lead a five-year, cross-divisional project focused on organ damage caused by sickle cell disease.
Research From New Center Of Excellence Could Prevent Kidney, Heart Damage
The deadliest thing about sickle cell disease is not just the misshapen red blood cells it produces that cause vascular occlusions. Another threat appears to come from oxidative stress.
Recent research shows that sickle cell disease changes the way reactive oxygen species (ROS) interact with the system that regulates blood pressure and fluids in the body, the renin angiotensin system. Over time, the activity of this harmful molecular pathway destroys kidney and heart function.
Five divisions at Cincinnati Children’s are now studying this process. They will use a five-year, $9.1 million grant from the National Heart, Lung and Blood Institute (NHLBI) to create the Cincinnati Center of Excellence in Hemoglobinopathy, one of nine cooperative projects nationwide exploring promising research in hemoglobin disorders.
“We found that the same renin angiotensin system that causes renal damage in diabetes and hypertension also is activated by sickle cell,” says Punam Malik, MD, a researcher in Experimental Hematology and principal investigator for the new grant. “More importantly, we found that blocking this signaling pathway in mouse models prevents organ damage when they are transplanted with sickle cell disease.”
Scientists from the Heart Institute, the Cancer and Blood Disease Institute, and the Divisions of Experimental Hematology, Hematology, Radiology and Developmental Biology will explore how this signaling pathway can be manipulated in mouse models, and whether a similar pathway exists and can be controlled in humans with sickle cell disease. They also will explore novel non-invasive imaging tools to detect early signs of cardiac damage in people with sickle cell disease.
Sickle Cell Grant Scientists
Punam Malik, MD.
Jeffrey Towbin, MD, Cardiology
Jay Degen, PhD, Experimental Hematology
Charles Quinn, MD, Hematology
Theodora Kalfa, MD, PhD, Hematology
Michael Taylor, MD, Cardiology
Steven Potter PhD, Developmental Biology
Robert Fleck, MD, Radiology
Omar Niss, MD, Hematology
Pariah Arumugan, PhD, Experimental Hematology
Detecting Liver Disease Without Needle Biopsy
|Drs. Daniel Podberesky and Starve Xanthakos use magnetic resonance elastography to find liver damage. Red area shows stiffness and scarring.
Magnetic resonance elastography (MRE) accurately detects liver scarring in children with chronic liver disease, without the risks and expense of a needle biopsy, according to researchers at Cincinnati Children’s.
The technique has proven especially useful for children who have non-alcoholic fatty liver disease (NAFLD). The disease, which can lead to liver failure and is fueled in large part by obesity, affects an estimated 13 percent of adolescents. A study published online in September in the Journal of Pediatrics shows that MRE effectively and accurately detects the condition.
“Because many pediatric patients with NAFLD are severely obese, MRE is likely to be superior to ultrasound-based elastography in this population,” says gastroenterologist Stavra Xanthakos, MD, lead author of the study. Ultrasound-based methods are less reliable in severely obese patients.
The researchers evaluated 35 patients aged 4 to 20 for chronic liver disease using both MRE and liver biopsy. They found MRE highly accurate in detecting advanced fibrosis, even in severely obese patients. The technique measures tissue stiffness and takes only a few minutes. If the findings are validated in larger studies, MRE could reduce dependence on needle biopsies, the standard practice for evaluating liver fibrosis.
“Having the ability to easily and non-invasively assess the degree of fibrosis in a child’s liver could help us identify the issue early and determine the right course of treatment in a timely manner,” says Daniel Podberesky, MD, chief of thoracoabdominal imaging at Cincinnati Children’s and a co-author of the study.
Muglia Named To Institute Of Medicine
|Dr. Louis Muglia is one of seven Cincinnati Children’s faculty members in the Institute of Medicine.
Louis Muglia, MD, PhD, Co-Director of the Perinatal Institute and Director of the Center for Prevention of Preterm Birth at Cincinnati Children’s, has been elected to membership in the Institute of Medicine (IOM) of the National Academy of Sciences.
Muglia has pioneered in vivo analyses of regulation of the endocrine stress response and the molecular pathways leading to birth. His laboratory studies the biological process controlling the timing for birth in humans. Among his achievements are more than 175 publications and recognitions that include election to the American Society for Clinical Investigation and Association of American Physicians. In 2010, he was elected to Fellow in the American Association for the Advancement of Science. Muglia is chairman of the Board of Scientific Counselors for the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.
In May, Muglia was appointed coordinating principal investigator for the $10 million March of Dimes Prematurity Research Center Ohio Collaborative, a research program aimed at finding the unknown causes of premature birth.
Muglia joins six Cincinnati Children’s faculty previously elected to the IOM: Uma Kotagal, MD, (2009), Arnold Strauss, MD, (2007), Alan Jobe, MD, PhD, (2007), Jeffrey A. Whitsett, MD, (2003), Thomas Boat, MD, now dean of the University of Cincinnati College of Medicine and Vice President for Health Affairs, (2001), and Margaret Hostetter, MD, (2000).
Blocking Protein May Halt Aggressive Form Of Leukemia
|Targeting the RUNX1 protein could stop the progression of AML, says Dr. James Mulloy.
A protein that regulates blood cell development could provide a way to treat acute myeloid leukemia (AML), according to a study led by researchers in our Division of Experimental Hematology and Cancer Biology.
The findings, posted online in August in the Journal of Clinical Investigation, found that the RUNX1 protein plays an unexpected role in supporting the growth of AML.
“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,” says James Mulloy, PhD, the study’s lead investigator.
AML develops and progresses rapidly, requiring prompt treatment with chemotherapy, radiation or bone marrow transplant. Treatment can be risky or only partially effective. Mulloy and colleagues are searching for targeted molecular approaches that could be more effective and carry fewer side effects.
They developed a mouse model of AML driven by fusion proteins and the leukemic gene MLL-AF9. When researchers genetically inhibited RUNX1 and an associated protein in the mice, it stopped the development of leukemia cells.
Mulloy says the findings demonstrate that RUNX1 merits further research as a potential target for treatment of AML.
Lung Transplant Program Launches
|Dr. Marc Schecter will serve as the lung transplant program’s Medical Director.
Cincinnati Children’s has launched one of the few pediatric lung transplant programs that will perform transplants for infants as small as 11 pounds.
Marc Schecter, MD, formerly at Texas Children’s Hospital, is Medical Director. David Morales, MD, is the Surgical Director.
Currently, only two US hospitals perform more than 10 pediatric lung transplants a year, a goal we plan to reach within three years. The program also will make it possible for the medical center to perform heart-lung and other multiple organ transplants.
Schecter has participated in more than 90 pediatric lung transplants; Morales has been involved in more than 50. Schecter plans to continue research that explores the risk factors affecting transplant outcomes and the impact of transplants on quality of life.
Cincinnati Children’s program for pulmonary disease is one of the nation’s largest and was recently ranked No. 2 in the nation by U.S. News & World Report. The medical center also has extensive experience in pediatric organ transplantation, including more than 530 liver transplants, 278 kidney transplants, 90 heart transplants and 30 intestinal transplants.
Study Identifies Protein Crucial To Healthy Blood Cell Production
|Repairing deficiencies in the RhoA protein could cure many blood disorders, says Dr. Yi Zheng.
A protein that controls the formation of mature blood cells could play an important role in new treatments for blood diseases.
A study led by researchers from Cincinnati Children’s, published online in October in the Journal of Experimental Medicine, clarifies the function of RhoA, a GTPase protein that serves as a molecular switch guiding blood cell formation.
Mutations in the RhoA pathway have been linked to certain immune disorders, including human combined immunodeficiency. Finding ways to control the pathway could lead to improved treatments for blood diseases, immune disorders and cancers.
“We show that RhoA deficiency causes hematopoietic failure in all lines of blood cells and results in defective hematopoietic progenitor cells,” says Yi Zheng, PhD, Director of Experimental Hematology and Cancer Biology and the study’s lead investigator. “This is important to understanding diseases like pancytopenia, in which people don’t produce enough mature red and white blood cells and platelets.”
Zheng and colleagues transplanted stem cells from mice bred to lack RhoA into another group of mice. The RhoA-deficient stem cells engrafted long-term, but did not produce new progenitor cells or differentiated blood cells. In another test, the researchers were able to reconstitute RhoA in the cells, which restored the normal function of hematopoietic stem and progenitor cells.
Zheng’s team is now testing prospective small-molecule inhibitors developed at Cincinnati Children’s that could treat disease by blocking abnormal RhoA pathway functions.
Obesity A Major Factor In Earlier Onset Of Puberty In Girls
|Dr. Frank Biro has found that girls’ early maturation due to obesity is fraught with physical and emotional risks.
Obesity is the largest predictor of early onset puberty in girls, according to a study led by Cincinnati Children’s adolescent medicine specialist Frank Biro, MD.
Results of the multi-institutional study were published online in Pediatrics in November. The findings add to a growing body of research documenting the earlier onset of puberty in girls of all races.
“The impact of earlier maturation in girls has important clinical implications involving psychosocial and biologic outcomes,” says Biro.
Girls who mature earlier are at risk of lower self-esteem, higher rates of depression, norm-breaking behaviors and lower academic achievement. Early maturation also increases risk of obesity, hypertension and breast, ovarian and endometrial cancer.
Researchers followed 1,239 girls in San Francisco, Cincinnati and New York City from 2004 to 2011. The girls were between 6 to 8 years of age at enrollment and were evaluated at regular intervals using established criteria of pubertal maturation.
They found that the age of onset of breast development varied by race, body mass index (obesity), and geographic location. But body mass index was a stronger predictor of earlier puberty than race or ethnicity.
Breast development began in white, non-Hispanic girls at a median age of 9.7 years, earlier than previously reported. Black girls in the study continued to start breast development at a median age of 8.8 years; Hispanic girls, 9.3 years; and Asian girls, 9.7 years.
Although the research team is still working to confirm the exact environmental and physiological factors behind the phenomenon, they conclude the earlier onset of puberty in white girls is likely caused by greater obesity.
Other institutions participating in the study were Kaiser Permanente Division of Research, Oakland, Calif.; Mount Sinai School of Medicine, New York; California Department of Public Health and the University of California at Berkeley and San Francisco; and the University of Cincinnati College of Medicine.
New Director Of Biomedical Informatics
|Dr. Peter White will hold a dual appointment in biomedical informatics at Cincinnati Children’s and the University of Cincinnati.
Peter White, PhD, became Director of the Division of Biomedical Informatics at Cincinnati Children’s, and the Rieveschl Chair of the newly created Department of Biomedical Informatics at the University of Cincinnati’s College of Medicine, effective Feb 1, 2014.
White comes to Cincinnati Children’s from the Children’s Hospital of Philadelphia, where he launched the Research Institute’s Center for Biomedical Informatics in 2006. He oversaw that Center’s expansion in genome analysis, translational informatics, application development, mobile health, data reporting and management, and informatics education.
“I’m most excited about the opportunity to further develop biomedical informatics capabilities at Cincinnati Children’s,” White says. “It is apparent that the hospital and the University are well positioned to make better use of research and clinical data for new discoveries and innovative science. Cincinnati Children’s high quality of translational and clinical research, along with exceptional clinical care, provides our new department with many opportunities to improve the lives of children through more thoughtful use of biomedical data.”
White’s research includes identifying the genomic contributors to risk for pediatric disorders that include neuropsychiatric disorders, cardiac defects, and solid tumors. White and his research team have developed methods for extracting, integrating and disseminating biomedical data using novel informatics approaches.
White has an undergraduate degree in biology and received a PhD in Molecular Genetics at Washington University in St. Louis in 1992. He plays a lead informatics role on a number of NIH consortia, including the Newborn Screening Translational Research Network, the NHLBI Bench to Bassinet Program, the Clinical Sequencing and Exploratory Research Consortium, and the Audiology and Genetics Database.
Mutations Linked To Rare Deafness Could Damage Other Organs
|Mutations in the TRIC gene can cause deafness as well as heart and thyroid problems, says Dr. Saima Riazuddin.
A molecular process that causes an uncommon form of deafness may put affected individuals at higher risk of damage to the heart, thyroid and salivary glands, according to a multi-national research team led by scientists at Cincinnati Children’s.
The study, posted online in August in the Journal of Clinical Investigation, focused on finding possible treatments for DFNB49 non-syndromic hearing loss, an inherited condition caused by mutations in the gene TRIC. But the mouse model developed for the research demonstrated unexpected characteristics that suggest TRIC mutations also can damage cell structures in other organs.
“Our study in mice suggests we should clinically evaluate affected individuals more thoroughly, as they may have other, not very obvious clinical problems,” says Saima Riazuddin, PhD, senior investigator and a scientist in the Division of Otolaryngology/Head and Neck Surgery at Cincinnati Children’s.
The researchers developed a mouse model that cannot produce a critical protein, tricellulin. As expected, the loss of tricellulin disrupted the formation of cochlear hair cells, which resulted in hearing loss. But the researchers also saw damage to other organs.
Riazuddin states that earlier studies of DFNB49 families did not reveal conditions besides hearing loss, but the human families were not assessed to the same extent as were the tricellulin mutant mice.
“We are beginning to understand the broader function of tricellulin,” she says, “and this study will guide us for further follow-up clinical evaluations of affected families.”
Evidence Of Environmental-Genetic Connection To Preterm Birth
|Dr. S.K. Dey’s animal study provides the first scientific evidence of the impact of genes and environmental stress on preterm birth.
Environmental stress, combined with a genetic predisposition, has long been suspected of contributing to preterm birth.
Now, a research team at Cincinnati Children’s has evidence of this gene-environment interaction. In animal studies led by Sudhansu K. Dey, PhD, Director of Reproductive Sciences, the combination resulted in preterm births 100 percent of the time.
“The concept had not been experimentally interrogated,” says Dey. “Our studies in mice provide evidence that when a genetic predisposition is combined with mild inflammation, the rate of preterm birth is profoundly increased, provoking preterm birth in 100 percent of the females.”
Dey added that the molecular signatures observed in their mouse studies were consistent with those in tissue samples from women who had preterm deliveries.
The researchers also found a treatment strategy that appears to prevent preterm delivery. They published their findings in the Journal of Clinical Investigation in August.
Others participating in the study were first author Jeeyeon Cha, an MD/PhD candidate in Dey’s laboratory, and Yasushi Hirota, MD, PhD, of the Department of Obstetrics & Gynecology in the Graduate School of Medicine at the University of Tokyo.
The investigators developed a mouse model of preterm delivery in which they inactivated the Trp53 gene in the uterus. Trp53 encodes a protein that regulates cell growth and replication. The preterm birth rate in the mice went to 50 percent just from the genetic deletion. When they subjected the Trp53-deficient mice to mild inflammation with an endotoxin, the preterm birth rate jumped to 100 percent.
The scientists then designed a treatment combining rapamycin and progesterone, which was effective at preventing preterm birth in the mice, with no apparent adverse effects on maternal or fetal health. This suggests that a combined therapy with low doses of an mTORC1 inhibitor and progesterone may help reduce the incidence of preterm birth in high-risk women.
New Projects Tackle Sickle Cell Disease In Africa
Three Studies In Four Nations Seek To Prove Value Of Effective, Inexpensive Treatments
|75 percent of the world’s children born with sickle cell disease are in Africa, says Dr. Russell Ware, and most die by age 5. His studies aim to get treatment to those children.
Here in the US, most children born with sickle cell disease can expect to live at least into their 40s or 50s. But in Africa, the vast majority of children born with the disease die before they reach age 5.
It doesn’t have to be that way, says Russell Ware, MD, PhD, the new Director of Hematology at Cincinnati Children’s and Executive Co-Director of the Cancer and Blood Diseases Institute. Simply expanding the use of simple blood tests and inexpensive treatments could give hundreds of thousands of African children a chance to grow up.
Ware joined Cincinnati Children’s in July 2013, bringing with him years of experience working with sickle cell and other blood diseases. Two years ago, he helped launch a screening and treatment program in Angola that has shown promising results. He expects to accelerate that effort with three new projects in 2014.
Uganda Sickle Surveillance Study (US3)
Using funds from our Cancer and Blood Diseases Institute, Ware will launch an 18-month mapping study with the Ugandan Ministry of Health. The project will analyze blood sample cards collected from babies born to HIV-infected mothers. This will help identify the distribution of sickle cell throughout Uganda and help launch sickle cell screening programs.
Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM)
Ware is co-principal investigator for a two-year, placebo-controlled clinical trial in Uganda to evaluate whether hydroxyurea treatment for sickle cell disease makes children more susceptible to malaria. Up to 200 children will be involved. Ware is working with Chandy John, MD, MS, a malaria expert at the University of Minnesota, and a team in Uganda on this Doris Duke Charitable Foundation-funded project.
Realizing Effectiveness Across Continents with Hydroxyurea (REACH)
This Phase I/II clinical trial will involve up to 450 children in Angola, Kenya and the Democratic Republic of Congo to determine safe and effective dose levels of hydroxyurea in regions with high rates of malaria and malnourishment. Ware is working with colleagues at The Hospital for Sick Children in Toronto on this study.
The potential to make a difference against sickle cell in Africa is large because much of the medical care for the disease is not complicated or expensive, Ware says.
”Hydroxyurea is taken once a day by mouth and it costs about $1 a day. Once we get the right dosing and show that it’s safe, I think it will catch on and save many, many lives.”
Big Step Forward In Fighting Norovirus
|Early tests of a norovirus vaccine show promise in preventing the illness or reducing its severity, says Dr. David Bernstein.
Results from a recent “challenge” trial led by researchers at Cincinnati Children’s reveal that an investigational norovirus vaccine appears well tolerated and effective against the most common strain of the virus.
The study, led by David Bernstein, MD, MA, involved 98 people who drank water dosed with norovirus, 50 of whom received the injected vaccine while 48 received placebo injections.
Among those who received the vaccine, 26 people were infected, the researchers said. In the other group, 29 people were infected. However, just 10 people who were vaccinated developed mild, moderate or severe vomiting and/or diarrhea, compared with 20 people in the placebo group. This means the vaccine achieved a 52 percent efficacy in preventing disease. It was even more effective in preventing severe disease.
Norovirus is a common and highly contagious cause of gastrointestinal illness that causes 200,000 deaths a year worldwide.
The challenge trial involved volunteers who agreed to spend five days in a controlled, hospital-like setting. The next step will be to test the vaccine in a larger clinical trial under real-world conditions.
“Ideally, we would like a vaccine to do a little better than 50 percent symptom reduction, but a vaccine that reduces severe symptoms could save many lives and help keep many more people out of the hospital,” says Bernstein.