IOA Pilot Research Grantees 2007
The IOA is pleased to announce the following as awardees of a 2006-2007 Pilot Research Grant. With the generous support of The Bingham Trust, the IOA was able to award 9 Pilot Research Grants for 2007. Click on the IOA newsletter at right for additional information.
To read abstracts of the winning Pilot Research Grants, click on the awardees' names below:
David Allman, PhD, School of Medicine
Anne Cappola, MD, ScM, School of Medicine
Christoper Coleman, PhD, MPH, APRN-BC, ACRN, School of Nursing
Dawn M. Elliott, PhD, School of Medicine
Thomas F. Floyd, MD, School of Medicine
Brad Johnson, MD, PhD, School of Medicine
Paul S. Schmidt, PhD, School of Arts and Sciences
Daniel Weintraub, MD, School of Medicine
Robert B. Wilson, MD, PhD, School of Medicine
"Aging of hematopoietic stem cells"
Throughout most of adult life hematopoietic stem cells (HSCs) produce all red and white blood cells. However, with aging HSCs selectively lose the capacity to generate two types of white blood cells known as B and T cells. Both B and T cells are key components of the adaptive immune system. The primary objective of our study is to determine why HSCs lose the capacity to generate B cells with age. Our experiments will test the hypothesis that aging leads to a decline in the activity of two proteins known to be required for early B cell development from HSCs. These proteins are named E47 and EBF. Understanding why E47 and EBF activity decreases with age will provide fundamental information on how aging impacts HSC function. As a result these studies will provide insights into potential clinical strategies to improve bone marrow transplantation and overall immune system function in the elderly.
"Ghrelin in the Frailty Syndrome: A Pilot Study"
Pilot Awardee Anne Cappola, MD, ScM finds appetite-stimulating hormone, ghrelin, as first potential medical treatment for frailty in older women.
"Reducing HIV Transmission Behaviors Among HIV Seropositive African American men Fifty Years and Older"
With the use of antiretroviral therapy, infection rates and mortality from acquired immunodeficiency syndrome (AIDS) are stabilizing in the United States (U.S.), but aging adults receive little attention in the area of infection prevention and control. While much of the focus has traditionally been on younger adults, the incidence and prevalence among fifty years and older adults with HIV (Human Immunodeficiency Virus) infection and AIDS (Acquired Immunodeficiency Syndrome) are increasing. The purpose of this study is to establish the basis for an innovative intervention to be used with 60 Black (non-Hispanic) men fifty-years and older who are HIV seropositive. To date, there are no nationally tested innovative interventions for this age group, making this project urgent in light of current demographics concerning prevalence in this population.
"Intervertebral Disc Aging and Degeneration: Pilot study to evaluate a novel treatment to restore mechanical function and structure"
The primary function of the intervertebral disc is mechanical: allowing motion and providing load support in the spine. The altered loading associated with aging and degeneration has a potential link to back pain. Neither conservative treatments nor surgical options restore disc structure or mechanical function. Minimally invasive therapies that slow or reverse degeneration and restore disc mechanics would be of significant benefit. The objective of this exploratory proposal is to restore disc mechanics, structure, composition, and alter cell activity in an in vivo model of disc degeneration using an injectable crosslinking agent. This study will test a novel therapeutic approach to a major health problem. Future studies, should this injectable therapy prove successful, will move toward clinical studies for human disc degeneration and will explore biological mechanisms and cell activity under this therapy.
"Aging & the brain’s hypoxic response to anemia"
Fifty to eighty percent of patients experience postoperative cognitive dysfunction in the weeks after cardiac surgery, and while less frequent after noncardiac surgery, the occurrence is also significant. There is consensus that advanced age is the primary risk factor for this sequelae, yet responsible mechanisms remain poorly understood. There is also concern that neurological injury after surgery may lead to further long-term cognitive decline or dementia. Major surgery is often associated with the occurrence of a rather acute anemia. We suggest that acute anemia may have an important role in postoperative cognitive dysfunction across the various surgical disciplines. Preliminary data from our laboratory demonstrates that acute isovolemic anemia results in a marked impairment in the ability to acquire new memory in the aged rat with hypertension.
Evidence suggests that aging may impair the ability of cells to coordinate protective responses to lower than normal oxygen levels(hypoxic response). Injury may then occur and may play an important role in accelerating aging, to include accelerating the onset of dementia. Anemia, such as is created in major surgery, may initiate and require an efficient hypoxic response to prevent injury and cognitive impairment. Inefficiency of hypoxia sensing mechanisms with aging in response to anemia may contribute to the increased risk of cognitive dysfunction in these patients. We will test the hypotheses that moderate, clinically relevant levels of acute anemia initiate a cerebral hypoxic response that is impaired with aging and results in an accelerated rate of cell death.
Relevance: As the population ages, the numbers presenting for major surgery and at high risk for cognitive dysfunction continues to increase. Full recovery from surgery is prolonged and quality of life impaired by this disorder. Early reports suggesting that the onset of dementia may be accelerated by this disorder necessitates further investigation. If anemia contributes to this disorder there may be relatively safe and efficacious therapeutic interventions, such as erythropoietin, to ameliorate recovery.
"Tissue repopulation and phenotypic rescue by bone marrow derived cells in a mouse model of premature aging"
We have developed a mouse model that suffers from the premature onset of age-related diseases. The mice lack the function of two genes, called Wrn and Terc, which in normal individuals act to prevent aging. There are rare examples of people who lack the function of one of these genes and so develop age-related diseases more rapidly than normal: individuals lacking Wrn develop Werner syndrome, while individuals lacking Terc develop dyskeratosis congenita. The combined loss of these genes in mice causes defects in many tissues, including impaired immune function, osteoporosis, and defective maintenance of the digestive tract, skin and liver. Our work will test if the defects can be repaired by transplantation of bone marrow from normal mice into the mutants. The bone marrow contains cells that can apparently travel through the bloodstream to tissues throughout the body where the cells can contribute directly to the function of these tissues. We believe that normal bone marrow cells will thus reverse some of the tissue defects in the mutants. Our findings should help guide the use of transplanted cells in the treatment of age-related diseases in people.
"couch potato aging in Drosophila"
Reproductive diapause or quiescence is a genetically programmed syndrome during which reproduction is suspended, stress resistance is elevated, and lifespan is extended. In the model organism Drosophila melanogaster, the propensity of a given line or genotype to enter reproductive diapause has a significant impact on a variety of traits including lifespan, rates of senescence, stress resistance, reproductive output, lipid content, and development time. Recently, it was determined that the observed variation for reproductive diapause was determined by a single gene, couch potato; the ability to express diapause results from a reduction in the expression or activity of the gene. As the phenotype of diapause has such widespread and pronounced effects on longevity, rates of aging, and correlated traits, any identified gene for diapause is also a candidate gene for aging. The proposed research seeks to address two questions: 1) what is the impact of variation in cpo expression on lifespan, rates of senescence, and associated traits? 2) what is the functional significance of naturally occurring cpo allelic variants on these traits? The Drosophila cpo gene exhibits homology to genes in other organisms, including vertebrates, and has been shown to impact the rate of progression of neurodegeneration. As diapause and cpo have such widespread impacts on aging and age-dependent traits, this research this research may also be of significance to the study of diseases or disorders that are age-dependent.
"Use of 123I ADAM SPECT Imaging to Measure Changes in Serotonin Transporter (SERT) Binding with Treatment of Depression in Parkinson’s Disease"
The aim of this study is to better understand the chemical changes in the brain that occur as part of depression in Parkinson’s disease (PD), and whether those changes are reversible with treatment. Parkinson’s disease patients with depression who are enrolled in one of two treatment studies (one medication therapy and the other talking therapy) will undergo a brain scan to measure the function of the brain serotonin system, which is closely linked with depression. Subjects will be scanned both before and after study participation, so it will be possible to examine both the connection between depression in PD and changes in the serotonin system, and whether successful depression treatment leads to a normalization of these serotonin changes.
"Screening assays for NADH-ubiquinone oxidoreductase deficiency"
Cells need energy to function. The part of the cell that provides energy is called the mitochondrion (plural: mitochondria). Through a series of biochemical reactions, mitochondria convert breakdown products from the food we eat into chemical energy for the cell. Mitochondrial energy production is particularly important for heart and skeletal muscle cells, and for nerve cells (neurons). The biochemical reactions for mitochondrial energy production are carried out by protein complexes known as Complexes I, II, III, IV, and V. The activities of these five protein complexes must be maintained in a precise balance for proper mitochondrial energy production.
For the last ten years, I’ve studied Friedreich’s ataxia, an inherited disorder characterized by childhood-onset ataxia (uncoordination), progressive weakness of heart and skeletal muscle with eventual heart failure, and diabetes and/or impaired glucose tolerance. The signs and symptoms of Friedreich’s ataxia are caused by mitochondrial dysfunction (particularly in Complexes I, II, and III) in neurons involved in coordination, in heart and skeletal muscle cells, and in insulin-secreting cells. Through funding from the National Institute for Neurological Disorders and Stroke, I constructed, validated, and implemented a high-throughput drug screen (of 102,000 compounds) based on reversing the deleterious effects of mitochondrial dysfunction in Friedreich’s ataxia cells.
Loss of mitochondrial function is an important factor in aging as well. Mitochondrial function declines with age in the very cells that are most dependent on mitochondrial energy production – i.e., neurons and muscle cells – and aging is of course associated with decreased muscle strength, increased risk of heart failure, and decreased neuronal function, including neurons involved in coordination. In 2004, Trifunovic and colleagues constructed mice with defective mitochondria and the mice exhibited striking premature aging, further supporting the theory that loss of mitochondrial function is an important factor in normal aging. Thus, research on ways to reverse mitochondrial dysfunction in aging is a logical extension of my work on ways to reverse mitochondrial dysfunction in Friedreich’s ataxia. In fact, Friedreich’s ataxia can be thought of as a premature aging syndrome of large sensory neurons and heart and skeletal muscle.
Loss of mitochondrial function, particularly Complex I function, is also an important factor in Parkinson disease, for which advanced age is a risk factor. The chemical name for Complex I is “NADH-ubiquinone oxidoreductase.” Complex I activity is selectively decreased 15-30% in the part of the brain affected by Parkinson disease, and the most commonly used mouse models of Parkinson disease involve treating mice with chemicals that inhibit Complex I. Taken together, the data in the scientific literature suggest that Complex I deficiency contributes to Parkinson disease and is therefore a logical target for further analysis and for drug screening.
To identify potential drug targets, and potential drugs, that help reverse the deleterious effects of Complex I deficiency, Dr. Grazia Cotticelli and I developed a screening assay for Complex I deficiency using a yeast model system and applied for a Molecular Libraries Screening Centers Network (MLSCN) Resource Access Award from the NIH. The NIH application was well received but unsuccessful. The primary criticism was the lack of data in support of a secondary screening assay in mammalian cells. Hence the aim of our present work is to develop and validate mammalian-cell-based models of Complex I deficiency suitable for secondary drug screening. Our immediate goal is to generate data to support a successful resubmission of our MLSCN proposal to the NIH. Our long-term goal is to identify effective treatments for Parkinson disease that target the Complex I deficiency that contributes to the signs and symptoms of the disease. Such treatments might also be effective in other conditions and diseases associated with aging and mitochondrial dysfunction.