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January 23, 2003


$1.8 million granted for study of heart disease risk in women with lupus

Researchers at Pitt’s Graduate School of Public Health (GSPH) have received a $1.8 million grant from the National Institutes of Health (NIH) for a five-year study of how genetic variations contribute to the risk of coronary heart disease (CHD) in women with systemic lupus erythematosus.

Systemic lupus erythematosus is a prototypic systemic inflammatory autoimmune disease that affects mainly premenopausal women. It is three to four times more prevalent among African-Americans than among whites. The risk of CHD in women with lupus is up to 50 times higher than in the general population.

The newly funded study will examine how genetic variations modify the risk of CHD among women with lupus.

Antiphospholipid antibodies (APA) are found in half of all women with lupus, compared with only 1-5 percent of the general population.

APA are produced mainly against the apolipoprotein H (apoH) protein in people with autoimmune diseases such as lupus. Under normal circumstances, apoH inhibits the uptake of oxidized low-density lipoprotein (LDL) cholesterol (known as “bad” cholesterol) by cells in blood vessels. Conversely, in the presence of APA, apoH promotes the absorption of LDL.

“As the accumulation of oxidized LDL cholesterol is believed to initiate the atherosclerotic process, we believe that apoH-mediated immune response in patients with autoimmune diseases like lupus may lead to atherosclerosis,” said principal investigator M. Ilyas Kamboh, professor of human genetics at GSPH. “This study will determine whether individuals who are positive for APA and/or for antibodies to oxidize LDL cholesterol are prone to premature coronary heart disease and whether this susceptibility is modified by common genetic variation in the apoH gene.”

The study will be conducted in collaboration with Susan Manzi, co-director of the University of Pittsburgh’s Lupus Diagnostic and Treatment Center.


Research to develop microbicide barrier to HIV

The National Institutes of Health (NIH) has awarded a grant of nearly $8 million to Pitt and Magee-Womens Research Institute (MWRI) to fund research aimed at developing a microbicide barrier to the human immunodeficiency virus (HIV), the virus that causes AIDS.

The grant, through the NIH’s National Institute of Allergy and Infectious Diseases, marks the largest ever received thus far by project principal investigator Sharon Hillier, professor of obstetrics, gynecology and reproductive sciences and molecular genetics and biochemistry at Pitt’s School of Medicine.

Hillier and her colleagues will pursue several scientific projects that involve UC781, a tight-binding molecule discovered by co-principal investigator Michael Parniak, a professor of medicine in the Division of Infectious Diseases at Pitt. An organic molecule about the size of an antibiotic, UC781 is a non-nucleoside reverse transcriptase inhibitor that renders the HIV virus incapable of infecting cells. These projects include the following:

• Parniak will perform studies evaluating the microbial activity of UC781, alone and in combination with other active components, against a variety of strains of HIV. This project is designed to focus on the extraordinary genetic diversity of HIV and the corresponding need to inactivate a wide spectrum of viral strains. These early tests will be done in vitro to determine both the efficacy of UC781 against HIV and its safety for use.

• Phalguni Gupta, professor and assistant chairperson of the Division of Infectious Diseases and Microbiology at Pitt’s Graduate School of Public Health, will coordinate a project to determine toxicity and efficacy of UC781 on HIV transmission rates in pre-clinical studies.

• Lisa Rohan, assistant professor of pharmaceutical sciences in Pitt’s School of Pharmacy, and Charles Isaacs, of New York Institute for Basic Research on Staten Island, will work on ways to formulate UC781 with other active agents to improve potency, effectiveness and ease of use.

• Early clinical studies by Hillier and Harold Wiesenfeld, assistant professor of obstetrics, gynecology and reproductive sciences at Pitt’s School of Medicine, are planned using a formulation developed by project partner Biosyn Inc. to evaluate the safety and systemic absorption of UC781.

Since the federal government published the first report of five men having unexplained immune dysfunction in 1981, HIV and AIDS have devastated health and economic power across the globe. Worldwide, 20 million people have died and 42 million currently are estimated to be infected.

In 1986, women made up 7 percent of new AIDS cases. Recent studies from the United Nations and the World Health Organization have found that about half the people now infected with AIDS are women.

Other investigators involved are Marijane Krohn, associate professor of obstetrics, gynecology and reproductive sciences at Pitt’s medical school and an assistant investigator at MWRI; Bernard Moncla, research associate professor in the Division of Microbiology and Biochemistry at Pitt’s School of Dental Medicine, and Dorothy Patton of the University of Washington in Seattle.


SHRS to help people with disabilities overcome barriers to Internet

Studies show that the web is three times more usable for people without disabilities than for those with disabilities.

Researchers at Pitt’s School of Health and Rehabilitation Sciences (SHRS) Department of Health Information Management have been awarded two grants to help people with disabilities overcome these barriers.

The first grant, a $1.5 million grant from the National Institute on Disability and Rehabilitation Research, will evaluate barriers to using computers experienced by people with disabilities, as well as new and existing accommodations, which include assistive technology and training, to reduce these barriers. In addition, this grant will fund the creation of a gateway server that will make any web site, regardless of its level of accessibility, available to those with visual impairments, giving users a “window to the world.” This portion of the project also will be funded under a second, $490,000 grant from the National Telecommunications and Information Administration.

Bambang Parmanto, assistant professor in SHRS’s Department of Health Information Management and principal investigator of the project, said: “The Internet can help people with disabilities overcome environmental, educational and social barriers. Studies show that the Internet has the potential to increase the independence of individuals with disabilities by offering a wide variety of educational and employment opportunities and allowing individuals to participate in community activities.”

Under the project, researchers will maintain computer labs in three community-based locations: Pittsburgh Vision Services, Three Rivers Center for Independent Living and the Institute of Advanced Technology at the Community College of Allegheny County. At these labs, they will test the range of accommodation possibilities by matching the assistive device to the individual and providing coaching and mentoring. The project also will involve two national organizations: the American Foundation for the Blind and the National Federation of the Blind.

“There is a seed of change in disability research to accommodate the needs of consumers with disabilities at a level close to the foundation of a research project through what we call participatory action research,” said Miriam Hertz, an assistant professor in SHRS’s health information management department. “By having people who will be the end users of the product evaluate the product during its development we can best address their needs.”

In addition, a gateway web server will transform web content into the most accessible format for a given user. Initially, the software will focus on people with visual impairments, creating an adaptive server that responds to user preferences and delivers customized information. The server will be free to both users and developers.

“The development of this server is the backbone of this project,” Parmanto said. “Of the 25 most-visited web sites, none is accessible. Although there is a way to check sites for accessibility, many developers don’t want to take the time or spend the money to change their site, since they are not required by law to make the site accessible. Through this server, we can offer a cost-free alternative to updating their sites.”


Pitt to study genetics of aging in muscle, bone

Researchers at Pitt’s Graduate School of Public Health (GSPH) have received a grant of $2.4 million from the National Institutes of Health (NIH) for a five-year study of how genes are involved in the aging of the human musculoskeletal system.

The study is part of the ongoing national Health, Aging and Body Composition (Health ABC) study, also funded by the NIH.

Begun in 1997, Health ABC is an eight-year multi-center study of the impact of age-related declines in muscle mass, muscle strength, bone mass and bone weight on the health and activities of daily living in older people. In it, investigators are studying how sarcopenia, the progressive loss of muscle mass, and loss of bone mass contribute to disease and reduced independence among older European-Americans and African-Americans.

In the newly funded genetics component of Health ABC, researchers will examine how variation in 50 different genes contribute to differences in bone mineral density, bone quality, muscle mass, muscle strength and muscle quality and their decline with age.

“This genetics study will contribute to our knowledge of the mechanisms of age-related loss of lean body mass,” said principal investigator Robert E. Ferrell, who chairs GSPH’s Department of Human Genetics. “It will add to our understanding of the basic biology of aging and identify genetic targets for behavioral or pharmacological interventions to prevent age-related changes.”


Carbon monoxide has therapeutic benefits, Pitt study finds

Exposing rats to low levels of carbon monoxide (CO) prior to aorta transplantation prevents arteriosclerosis associated with chronic organ rejection and can also suppress stenosis after balloon-angioplasty-induced carotid artery injury, according to a study published in the Feb. 1 edition of Nature Medicine.

“These findings demonstrate a significant protective role for CO in vascular injury and support its use as a therapeutic agent,” according to study author Leo Otterbein, research assistant professor, Pitt School of Medicine, Division of Pulmonary and Critical Care Medicine.

The rats that received the aorta grafts were exposed to 250 parts per million (PPM) of CO immediately following transplantation and for the subsequent 56 days of the study. Those rats in the balloon injury portion of the study were exposed to the same PPM of CO for one hour prior to injury and then returned to room air for the subsequent two weeks.

As controls, researchers transplanted aortic segments from 10 Norway rats to Lewis rats, none of which were exposed to CO. Arteriosclerotic lesions began to appear after 20-30 days and were significant by 50-60 days. Lesions were characterized by intimal hyperplasia (vessel wall thickening), an increase in smooth muscle cells and leukocyte accumulation in the transplanted aorta. These processes are indications of arteriosclerosis and limit the success of transplants and angioplasties in humans. In the rats exposed to CO, intimal hyperplasia was significantly reduced by 61 percent.

In the second group of rats, their carotid arteries developed intimal hyperplasia 14 days after balloon injury. Intimal hyperplasia in rats exposed to CO for only one hour prior to injury was reduced by 74 percent over control rats exposed to air.

“Currently the best available treatment of clogged arteries is through angioplasty and a stent or via bypass surgery,” said Brian S. Zuckerbraun, general surgery resident at Pitt’s School of Medicine and co-author of the study. “But these have their limitations and a significant failure rate. If you could pre-treat patients with CO it might result in a better long-term outcome.”

“Our research suggests that the protective effect of CO relies on its ability to block leukocyte infiltration/activation as well as small muscle cell proliferation,” Otterbein said. “CO may prove to be beneficial in the treatment of a broad range of vascular diseases.”

In the study, there were no observed negative effects of the CO exposure on the animals. According to Otterbein, studies currently are underway with pigs.

Others involved in the research project at Pitt include Augustine Choi, chief of pulmonary, allergy and critical care medicine; Timothy Billiar, chairperson of the surgery department; Edith Tzeng, assistant professor of surgery in the vascular surgery division; post doctoral fellow Ruiping Song, and technician Fang Liu. This study was done in collaboration with a team of researchers at Harvard Medical School.

The study was supported by grants from the National Institutes of Health, an Atorvastin Research Award, sponsored by Pfizer, American Heart Association, and the Ethicon-Society of University Surgeons Resident Research Award.


TRACE to support development of infants, children with disabilities

North Carolina’s Orelena Hawks Puckett Institute, in collaboration with Pitt’s UCLID Center and Children’s Hospital of Pittsburgh, has been awarded a five-year grant from the U.S. Department of Education, Office of Special Education Programs to establish a national research center on effective early childhood assessment practices.

The $3.5 million grant will enable researchers at four satellite centers to study and promote the use of the most beneficial practices for identifying and evaluating infants, toddlers and preschoolers who have, or are at-risk for, disabilities or delays.

They also will determine the best ways to match young children with disabilities and their families with appropriate supports through inclusive early care and education, early intervention, and early childhood special education programs.

The newly established center, to be known as TRACE Center for Excellence in Early Childhood Assessment (Tracking, Referral and Assessment), will unite researchers from the Puckett Institute with colleagues at The UCLID Center at Pitt and Children’s Hospital of Pittsburgh, along with researchers in North Carolina and Maryland.

Stephen J. Bagnato, Pitt professor of pediatrics and psychology, and director of the Early Childhood Partnerships program at UCLID, is director of the Pennsylvania TRACE satellite and research co-investigator. Bagnato’s satellite receives a $400,000 grant for the five-year research program.

The central mission of the TRACE Center is to support the healthy development of infants and young children with disabilities through effective early diagnosis, assessment and intervention.

TRACE researchers will collaborate with state and federal government officials to determine how standards and regulatory policies can enhance the use of effective early childhood assessments to identify young children with special needs and to better plan their programs and track their progress.


Stem cell research funded

Two faculty members of Pitt’s School of Medicine have received grants totaling more than $2 million from the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health to fund studies that target the use of stem cells to treat disease.

They are Christopher Niyibizi, research associate professor in the Ferguson Laboratory for Orthopaedic Research in the Department of Orthopaedic Surgery and Cell Biology and Physiology, and Johnny Huard, Henry J. Mankin Associate Professor of Orthopaedic Surgery. Huard also is an associate professor in Pitt’s Department of Molecular Genetics and Biochemistry, deputy director of the McGowan Institute for Regenerative Medicine and director of the Growth and Development Laboratory at Children’s Hospital of Pittsburgh.

Niyibizi, who also is a faculty member of the McGowan Institute, has been awarded $1.26 million for a study, “Stem Cell Therapy for Diseases of Bone in a Mouse Model.” This study is evaluating the use of stem cells derived from adult bone marrow for the treatment of osteogenesis imperfecta (OI), a hereditary disorder of the connective tissue related to collagen production that can be marked by extreme fragility of the long bones and a bluish color of the whites of the eyes. A person with OI can break a rib by coughing, or a leg by rolling over during sleep.

“Osteogenesis imperfecta can be a devastating illness — a constellation of illnesses,” Niyibizi said. “People can suffer hundreds of fractures throughout a lifetime in a truly disabling way.”

Niyibizi is principal investigator for the study, which focuses on mice that are born with a severe form of OI that mimics the human condition. Niyibizi and his colleagues are investigating the effect of using bone marrow-derived stem cells to treat these mice.

Previous studies have shown that mesenchymal stem cells isolated from bone marrow and infused into recipient animals persist in bone and differentiate into bone cells. Mesenchymal stem cells are undifferentiated cells that can become cells related to the connective tissue, including bone, cartilage, fat and muscle as well as brain and epithelial cells. The current study aims to determine characteristics of engraftment by these cells and their contribution to the animal’s bone structure.

The number of people affected by OI in the United States is estimated by the Osteogenesis Imperfecta Foundation as 20,000-50,000. There is no cure; treatment options are available ranging from medications to metal rod insertion surgery to strengthen skeletal support. Treatment of chronic fractures, physical therapy and the use of mobility aids also are common.

Other investigators include Janey Whalen, Paul Robbins and Molly Vogt, all of Pitt’s medical school, and Jeffrey Hollinger of Carnegie Mellon University.

This and other proposed studies will lead to the design of human clinical trials using bone marrow-derived cells for the treatment not only of OI, but also other bone-related disorders such as osteoporosis.

Huard has been awarded $1.2 million over five years for a study, “Muscle Regeneration Through Stem Cell Transplantation,” that focuses on using a unique population of muscle stem cells from healthy newborn mice to deliver dystrophin, a key protein for muscle function, into mice born with a genetic muscle-wasting disease similar to Duchenne muscular dystrophy. In humans, this genetic disease causes muscle weakness and early death because of respiratory or cardiac failure.

“Studying the behavior of these cells after transplant, we found some very exciting things,” said Huard. “Not only did the donor cells continue to grow and make dystrophin in the recipient, but they also apparently failed to provoke an immune response, which would protect them from rejection.”

In previous studies, transplant of these muscle-derived stem cells also improved muscle regeneration in recipient mice, Huard said. The current study targets further investigation of the use of such cell transplants to discover ways to improve prior results in muscle regeneration and dystrophin delivery.

Niyibizi’s and Huard’s studies also will further knowledge of basic stem cell behavior and function.

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