Institute on Aging Pilot Research Grantees 2013
The Institute on Aging was able to award 4 full Pilot Research Grants in support of aging and aging-related disease research. Congratulations to this year's awardees.
2013 Pilot Research Grant Awardees
This year's Pilot Research Grant Awardees are as follows:
Gastrointestinal viral infections, including rotaviruses and noroviruses, pose significant public health challenges in elderly patients. Norovirus (NoV) infections are the most common cause of non-bacterial gastroenteritis and are responsible for an estimated 23 million cases of acute gastroenteritis, leading to 50,000 hospitalizations and 300 deaths annually in the US alone. Although the majority of cases of NoV infection are self-limiting in healthy patients, NoV has been associated with more than 30% of deaths in elderly patients suffering from gastrointestinal symptoms. Despite the recognition that antiviral immunity can be severely dampened as a consequence of aging, efforts to increase immune system functionality in aged individuals have demonstrated limited success.
In this pilot proposal, we will test a novel hypothesis that brings together data from two fields of study; antiviral immunity in aging populations and the study of how gut-resident microbial communities can regulate immune responses. An emerging body of literature has provided data suggesting that aged populations exhibit limited diversity in the community structure of gut microbiota. In addition, deliberate manipulation of gut microbial communities in mice have demonstrated that signals derived from these gut-resident bacteria can significantly influence immune responses to a variety of pathogens. In this application, we provide preliminary data demonstrating that depletion of gut microbial communities through oral antibiotic treatment of mice results in decreased antiviral immunity to murine norovirus (MNV), a natural enteric pathogen of mice that serves as a model of human NoV infection. We propose to test the hypothesis that alterations in gut-resident microbial communities in aged mice has a role in decreased antiviral immune responses following MNV infection. We believe that this novel line of study will uncover new insights into immune regulation of aged populations.
Furthermore, through comprehensive analysis of the composition of gut microbial communities of young and aged mice, this work has significant potential to highlight new therapeutic targets to improve vaccination strategies to viral pathogens, including gastrointestinal NoV, in aged populations.
- Michael A. Lampson, PhD
"Maintaining Centromere Identity in Mammalian Oocytes During Aging"
Chromosome inheritance depends on an element within each chromosome known as the centromere. A protein that binds DNA, known as CENP-A, defines the location and function of the centromere. The process by which CENP-A is maintained on chromosomes in most dividing cells is well understood and explains how centromeres are propagated as these cells divide to create new cells. In one crucial exception, oocytes which divide to create eggs, there are major unresolved questions surrounding CENP-A maintenance during aging. Mammalian oocytes persist for the entire reproductive lifespan of the animal in a state in which the known mechanisms for CENP-A propagation do not apply. This proposal takes an innovative interdisciplinary approach, combining structural biology and biophysics with in vivo reproductive biology, to determine how centromeres are maintained in oocytes during aging. We will make the first measurements of CENP-A stability during oocyte aging, test whether an unconventional mechanism exists to replenish CENP-A during aging, and determine how CENP-A stability depends on its unusual structural features. The processes that we are studying are crucial for reproductive fitness and faithful chromosome inheritance between generations, and for understanding age-related disorders such as Down syndrome that are caused by errors in chromosome inheritance.
- Selamawit Negash, PhD
"Enhancing Cognitive Fitness in African American Older Adults"
With the aging of the “baby-boom” generation, there is an emerging interest in health promotion behaviors of older adults. The Alzheimer’s Association has recently partnered with the Centers for Disease Control and Prevention to develop the Healthy Brain Initiative, which recommends lifestyle interventions as part of its Road Map for maintaining or improving the cognitive performance of all adults. Despite the growing interest, however, research on cognitive health of minority older adults has critically lagged. This is unfortunate because minority populations are already at a disadvantage with regards to engaging in health promotion behaviors. The Penn Memory Center recently launched an innovative program, Cognitive Fitness, designed maintain and improve cognitive and emotional health in older adults. The program uses multi-modal approach and combines computer-based cognitive training, engagement in physical activity, and mindfulness meditation. Nonetheless, the program has a major limitation in that members of minority groups are underrepresented. This is a major health disparity concern, and interventions that are targeted towards ethnically diverse older adults are crucially needed, especially since studies suggest that minority elders may reap even greater benefits from well-developed cognitive wellness programs. The current proposal seeks to address this critical knowledge gap.
- E. James Petersson, PhD
"Using Semi-Synthetic to Understand the Formation and Propagation of Lewy Bodies in Parkinson's Disease and Dementia"
The maintenance of proteins in their stable, folded state is essential to proper cellular
function. Protein misfolding underlies at least 11 neurodegenerative disorders, including Alzheimer’s
disease (AD) and Parkinson’s disease (PD). AD and PD are the fifth and sixth leading causes of death
among Americans 65 and over, and care for the over 5 million AD and PD sufferers costs about 200
billion dollars annually with uncounted additional burden on the caretakers. The accumulation of
misfolded proteins in so-called amyloid forms is an inherent age-related phenomenon; without antiamyloid
therapeutics, success in other areas of medicine will only increase the number of patients afflicted by neurodegenerative disease in the coming decades. Current AD and PD treatments provide only symptom relief, and significant side effects are observed. Stem cell and neuronal grafting can replace some function, but can never fully recover memories that are lost with the original neurons. Drugs that reverse or block aggregation, combined with early diagnosis, provide the best prospect for a cure that preserves the patient’s precious memories. We propose to use our unique synthetic protein tools to obtain structural and mechanistic information on the misfolding of amyloid proteins. Understanding this process in chemical detail is fundamentally important to neuroscience because of the ubiquity of the amyloid phenomenon and provides our best hope for designing therapies that disaggregate amyloids or prevent propagation to “infect” healthy neurons. We will structurally characterize amyloid aggregates through distance measurements obtained using fluorescence energy transfer studies of labeled versions of amyloid proteins (Specific Aims 1 and 2). We will also identify other proteins whose interactions with amyloids are important for cell-to-cell propagation by photocrosslinking synthetic amyloids to capture their interaction partners (Specific Aim 3). To accomplish these goals, we must combine organic chemistry and molecular biology to synthesize proteins with fluorescent labels, crosslinkers, and purification tags. The Petersson laboratory has developed methods for adding these non-natural functions to proteins without disturbing the native protein behavior. We have achieved this by using very small probes, and we are now poised to apply these techniques to amyloidogenesis. In this pilot study, we will focus on alpha-synuclein, the aggregating species in PD and Lewy body dementia. We will examine a limited scope of conditions to show the feasibility of the type of experiments in each of our Specific Aims, which are technically demanding but potentially high in impact. Eventually, our methods should be applicable to all of the more than 20 proteins implicated in amyloid-type disorders. Furthermore, our tools should be equally valuable in understanding the native role of amyloidogenic proteins in healthy neurons, which is unknown for many of these 20 proteins. Finally, it is important that the impact of our research will not be limited to our own experiments, but that the protein tools we develop can be relatively easily shared with other researchers in the field, at UPenn and beyond.