June 15, 2009

NIH Funds $9.5 Million for Research on HIV and the Human Innate Immune System

Case Western Reserve's School of Dental Medicine receives largest grant in school's 117-year history

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Studying how the mouth wards off diseases will have implications for understanding overall how people stay healthy. The Case Western Reserve University School of Dental Medicine will use a five-year, $9.5 million grant from the National Institutes of Health's National Institute for Dental and Craniofacial Research—the largest grant ever in the dental school's 117-year history— to study oral health as one of the human body's frontline defenses against infections.

Under the direction of lead investigator Aaron Weinberg, professor and chair of the Department of Biological Sciences at the dental school, a team of 22 researchers will unravel changes in the human body's innate immune system in HIV-infected people on antiretroviral therapies to provide new insights into how the body keeps us healthy.

"New evidence surfaces repeatedly that oral health plays an important and integral role in general health," says Jerold Goldberg, dean of the dental school. "The award from the NIH demonstrates the importance of working across disciplines and professions to answer complex questions."

A multidisciplinary team from dentistry and medicine will discover why HIV-infected humans receiving the class of drugs referred to as highly active anti-retroviral therapy (HAART) have increased the incidence of oral complications, such as a quadrupled rate of contracting human papillomavirus (HPV). This virus is more frequently associated with the genital tract and is now being seen in the mouth. Warts produced by HPV can lead to cancer and increased oral infections.

"What is resolving one problem is setting off another," says Weinberg. "However, outcomes of our studies should help us better understand how the lining of our mouth and other parts of our body, like the skin, protect us from microbes that make us sick, and why some people are better protected than others."

The new study builds on seven years of previous research in which Weinberg and his colleagues discovered that human beta defensins (hBDs), frontline innate defense molecules found in epithelial cells linings in the mouth, inhibit infections from HIV. How this happens in the mouth may explain the protection seen in the mouth against the virus when compared to other body sites.

Four Research Projects

Through four research projects funded by the grant, researchers will examine changes in the frontline defense humans have against infections, such as hBDs and other innate immune molecules, found in the epithelial linings of the mouth, skin and urogenital track, which are constantly challenged by bacteria, fungi and viruses.

In two projects, researchers will design, produce and share altered forms of beta defensins. These altered hBDs will be used to study molecular interactions between beta defensins and key receptors on human cells that the research group had previously identified as important for bolstering innate defenses.

In the third and fourth projects, researchers will identify altered proteins in human epithelial cells from HIV-infected individuals on HAART, compare tissue samples from warts associated with HIV-positive (on HAART) and normal individuals, and find genetic differences between individuals, to explain why some people produce more hBDs than others that could better protect individuals from infections, such as HPV.

According to Weinberg, the projects are highly focused and collaborative and tap the expertise of researchers in innate immunity, defensin biology, structural chemistry, HIV immunology, dermatology, oral medicine and genetics.

Along with Weinberg, project leaders will be School of Medicine's Scott Sieg, Department of Medicine, and Tom McCormick, Department of Dermatology, and the School of Dental Medicine's Richard Jurevic, Department of Biological Sciences.

Weinberg and colleagues will identify changes in innate defense mechanisms that increase susceptibility to oral complications following HIV infection. "Discovering how this pathology occurs in the mouth, may offer the potential for understanding how similar complications arise in other body sites" says Weinberg.

In two projects, researchers will design, produce and share altered forms of beta defensins. These altered hBDs will be used to study molecular interactions between beta defensins and key receptors on human cells that the research group had previously identified as important in bolstering innate defenses.

In the third and fourth projects, researchers will identify altered proteins in human epithelial cells from HIV-infected individuals on HAART, examine tissue samples from warts associated with HIV, and find genetic differences between individuals, to explain why some people produce more hBDs than others that could better protect individuals from infections, such as HPV.

According to Weinberg, the projects are highly focused and collaborative and tap the expertise of researchers in innate immunity, defensin biology, structural chemistry, HIV immunology, dermatology, oral medicine and genetics.

Among the researchers' concerns is that prolonged use of HAART and/or low level chronic HIV infection may impact the human innate defense system, and the research team wants to know what happens.

Working with Mark Chance, professor and director of the Case Center for Proteomics and Bioinformatics, McCormick and Santosh Ghosh, postdoctoral fellow, Department of Biological Sciences in the dental school, the group has found significantly reduced protein expression in cells from HIV-infected individuals on HAART that impact the cell's cycle and immune responses.

"We now have proteomic data telling us that there is a dysfunction occurring in the epithelial cells," says Weinberg.

The researchers are interested in understanding what it means from a biological perspective because it will eventually provide a firm understanding of what proteins are really important in maintaining health and balance in the epithelial barriers of the body.

Using computational software they will detect the pathways and networks affected by chronic HIV infection and/or HAART and thereby, better understand the impact of the virus and the therapies used to combat HIV on epithelial defenses.

Under Goldberg's vision to build a strong research program at the dental school, Weinberg has strengthened the school's overall mission to advance research at the dental school. This grant furthers those efforts by enabling the dental school to establish an annual symposium, a monthly guest lectureship, and provide a career development program for faculty and training for students and postdoctoral fellows.

For more information contact Susan Griffith, 216.368.1004.

Posted by: Kimyette Finley, June 15, 2009 12:49 PM | News Topics: Collaborations/Partnerships, Faculty, Provost Initiatives, Research, School of Dental Medicine, School of Medicine, news

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