T H E   N I H   C A T A L Y S T      S E P T E M B E R  –  O C T O B E R   2005


For one day each August, NIH summer trainees—who run the gamut in educational level from high school through postgraduate schools—fill large common areas of the Clinical Center with hundreds of posters that tell the stories of the research they have been conducting with their NIH preceptors. For many, this research experience marks the beginning of a lifelong pursuit.


by Karen Ross


Vanessa Montalvo


Vanessa Montalvo, Howard University, Washington, D.C.

Immune Mediators’ Involvement in Retinal Damage: the Good and the Bad

Preceptor: Igal Gery, Laboratory of Immunology, NEI

Age-related macular degeneration (AMD) is the leading cause of blindness in Americans over the age of 55. People with AMD suffer from blind spots and distorted vision due to deterioration of the central part of the retina.

Although the cause of AMD is not known, one possibility is that decades of minor assaults on the retina from inflammation and light exposure may eventually cause the permanent damage characteristic of AMD.

Montalvo and her colleagues are investigating how the immune system both protects the retina from the types of injuries that may presage AMD ("the good immune system") and, conversely, contributes to these injuries ("the bad immune system").

CCL2, a chemical that recruits immune cells known as macrophages, also provides protection against cytotoxic processes and appears to belong in the "good" column.

Montalvo and her co-workers exposed normal mice and mice lacking the CCL2 gene to intense light and looked at the effect on their retinas. Normal retinas tolerated the light exposure to some degree, but in the retinas that lacked CCL2, the photoreceptor cells were almost completely obliterated.

On the other hand, C3, a member of the complement cascade, which is normally responsible for attacking and destroying invading bacteria and viruses, may have a negative effect on the retina.

Montalvo found C3 in retinas that were inflamed due to the transgenic expression of the immune molecule IL-7 and in retinas that were exposed to intense light.

Normal, undamaged retinas did not contain any C3.

Experiments to determine whether C3 is recruited to the retina after other kinds of damage are under way.

Karen Ross


More Insights on AMD

A new discovery that has excited us all has established the major role of complement in AMD. The discovery, published in three different papers in a Science issue (Volume 308, Issue 5720, April 15, 2005), is that an unusually strong correlation exists between AMD occurrence and a polymorphic variant of the gene for complement factor H (CFH).

The function of CFH is to block the activation of complement, and individuals who carry this variant have low CFH activity and, as a result, high levels of complement activation.

In addition, it has been known for several years that complement deposition is a common finding in retinas of AMD patients. Activated complement components initiate pathological processes, including recruitment of inflammatory cells and neovascularization, the major problem in AMD. It is assumed, therefore, that complement activation and deposition in the retina plays a major pathogenic role in AMD.

Montalvo’s study in mice is aimed at examining the possible deposition of complement in retinas damaged by various mechanisms.

So far, she has tested eyes damaged by light and inflammation induced by transgenic expression of IL-7. The deposition was found to be particularly intense in the IL-7 transgenic eyes.

Deposition of activated components of complement (including C3) is commonly seen in inflammation sites and is an integral part of the inflammation process because these deposited molecules further enhance the pathological process, mainly by recruitment of inflammatory cells.

Clinical implications of Montalvo’s research are expected to become more apparent when she tests eyes of mice that serve as "animal models" for AMD. We hope, therefore, that her study will shed new light on the process of complement deposition and its pathogenic role in AMD.

It is of interest that a recent study, by the group of Michael Gorin at the University of Pittsburgh (in press, Am. J. Hum. Gen.), discovered that AMD is also strongly related to variants at three genes, all on chromosome 10q26.

One of these genes, PLEKHA1, encodes the protein TAPP1, an activator of lymphocytes. These new data thus re-emphasize the suspected role of the immune response in the pathogenesis of AMD.

Research by Montalvo and her coworkers will be expanded to investigate the involvement of TAPP1 and related molecules in experimental models of retinal degeneration.

Igal Gery and Chi-Chao Chan

Laboratory of Immunology, NEI

Brenda Davis


Brenda Davis, Bethune-Cookman College, Daytona Beach, Fla.

Body Mass Index is a Superior Marker of Obesity in Women than Men

Preceptor: Anne Sumner, Clinical Endocrinology Branch,

Obesity is a contributing factor in a host of serious diseases, including heart disease and diabetes, and its prevalence is high and increasing.

Approximately 30 percent of Americans are classified as obese because they have a body mass index (BMI) greater than 30. BMI is calculated by dividing a person’s weight in kilograms by the square of his or her height in meters)

Currently, the same BMI standards are used to diagnose obesity in both men and women.

Davis’ research suggests, however, that women tolerate high BMI significantly better than men, suggesting that BMI, at least in its present formulation, may not be an adequate tool for predicting obesity-related disease.

Davis and her colleagues measured BMI and glucose intolerance, a marker of impending diabetes, in 141 African Americans—66 men and 75 women.

The BMI at which 50 percent of the subjects were glucose intolerant was 30 kg/m2 for the men and 40 kg/m2 for the women.

These results were especially surprising because, at any given BMI, men generally have a lower percentage of body fat than women, the team noted.

The group is now looking into the reasons why women seem to be less susceptible to the ill effects of obesity.

Davis, who will be a junior at Bethune-Cookman College in Daytona Beach, Florida, in the fall, commented that the study was particularly interesting to her because there are people in her family who have diabetes. "Now I have more insight into something that could affect me," she said.

—Karen Ross


Benjamin Mantell

Benjamin Mantell, Brown University, Providence, R.I.

Restoring Mitochondrial Integrity in the Insulin-Resistant State

Preceptors: Michael Sack, Ines Pagel, Cardiovascular Branch, NHLBI

Several lines of evidence suggest that mitochondrial dysfunction may be an important part of the pathology of type 2 diabetes.

First, total aerobic capacity, which measures how efficiently mitochondria use oxygen, is typically poor in people with diabetes.

Second, genes involved in the formation and function of mitochondria are downregulated at an early stage in the development of diabetes.

Third, a family of drugs used to treat diabetes—glitazones—may work by stimulating mitochondrial function.

Using mouse skeletal muscle cells as a model system, Mantell further explored the link between mitochondria and diabetes.

Feeding the muscle cells high levels of glucose causes them to become insulin resistant, one of the hallmarks of type 2 diabetes.

Insulin-resistant cells fail to appropriately adjust their metabolism in response to insulin.

Mantell found that the insulin-resistant cells had smaller-than-normal mitochondria, decreased oxygen consumption, and decreased expression of genes encoding mitochondrial proteins.

Treating the cells with one of the glitazones partially restored insulin sensitivity and corrected the mitochondrial defects.

Glitazones increase the activity of PPAR-g, a transcription factor that is important for the expression of mitochondrial genes. Therefore, Mantell next wants to deplete PPAR-g in cells.

He predicts that these cells will become insulin resistant and that glitazones will no longer be an effective treatment.

Mantell observed that because normal heart muscle cells are chock-full of mitochondria, defects in mitochondria could contribute to the poor prognosis in diabetic patients with heart disease.

Karen Ross



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