Institute on Aging Pilot Research Grantees 2012
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.
2012 Pilot Research Grant Awardees
This year's Pilot Research Grant Awardees are as follows:
Roy Hamilton, MD, MS, Penn School of Medicine
Hans-Peter Kohler, PhD, Penn School of Arts & Sciences
Nirinjini Naidoo, Penn School of Medicine
Harold Riethman, PhD, School of Medicine/Wistar Institute
- Roy Hamilton, MD, MS
"Transcranial Direct Current Stimulation to Enhance Language Recovery in Patients with Aphasia After Subacute Stroke"
Abstract:
The central aim of this proposal is to determine whether noninvasive electrical brain stimulation can be employed to enhance recovery from aphasia in the setting of subacute stroke. Aphasia is typically associated with left hemisphere injury and occurs in approximately 20% of patients with stroke, a highly prevalent disease that principally affects older individuals. Proposed mechanisms of aphasia recovery include recruitment of intact left hemisphere areas and, more controversially, acquisition of language abilities by right hemisphere structures. Interventions that facilitate these mechanisms may enhance recovery. This pilot proposal will explore the extent to which these two mechanisms can be enhanced in the subacute setting. Aphasic patients in an inpatient neurorehabilitation unit will receive anodal (excitatory) transcranial direct current stimulation (tDCS) to the left and right hemisphere, as well as sham tDCS. Stimulation will be paired with tests of naming and other language tasks to determine whether manipulation of either or both hemispheres is associated with either transient or persistent improvement in language. Demonstration of tDCS-induced effects on aphasia recovery could point the way toward future therapeutic approaches that may generalize to other stroke-related deficits and to other neurologic conditions affecting cognition.
- Hans-Peter Kohler, PhD
"Aging, Resource Networks and Mental Health in a Poor High-Risk Disease Environment"
Abstract:
Elderly individuals are not routinely screened for mental health and psychiatric disorders in resource-constraint settings such as sub-Saharan Africa (SSA), and the levels, age-trajectories, and correlates of mental health are poorly documented on the population level. This project will investigate how the high-HIV prevalence environment in SSA affects the mental health and well-being of older individuals in SSA. Using a unique longitudinal representative dataset from rural Malawi that provides extensive socioeconomic, social capital and health information - including the SF-12 mental health score, a well validated and standardized instrument commonly used to measure social and emotional functioning - the goals of this project include analyses of the impact of actual and/or perceived HIV+ status on mental health of older individuals, including the spill-over effects of actual and/or perceived HIV+ status of family/household members, and investigations of the impact of economic and health shocks, including changes in HIV+ status, on the health and well-being of elderly individuals in a low-income high-risk disease environment. Because in the absence of formal support and insurance mechanisms families in SSA rely on social networks and intergenerational transfers to cope with unexpected health and economic shocks, a lacking or limited access to such family resource networks is a potentially essential mechanism that explains the divergence in mental health outcomes among elderly in the SSA context. The project will therefore test the hypothesis that the availability of and/or access to family resource networks, intergenerational/lateral transfers and social support can buffer the impacts on mental health of the HIV/AIDS epidemic and its associated social and economic shocks. The proposed pilot grant will bring together a new team of researchers from Penn's Population Studies Center, Population Aging Center, Annenberg School for Communication, the Center for AIDS Resarch (CFAR), the Center for Mental Health Policy and Services Research, as well as the Centers for Disease Control and Prevention (CDC) and the Malawi College of Medicine, each with extensive and complimentary expertise. In addition to being important in its own right, the findings of this proposed research will provide essential preliminary data for the team's goals to focus the Malawi Longitudinal Study on Families and Health (MLSFH) renewal application in 2012 explicitly on aging, HIV and health in SSA.
Abstract:
The general population is aging, and diabetes is on the upswing in this group. Diabetes and pre-diabetes are major contributors to heart disease, stroke, kidney failure, and blindness - conditions that affect over 46% of U.S. adults and 76% of U.S. seniors at an annual cost of $174 billion. It has recently been recognized that sleep disruption has a major detrimental effect on glucose metabolism, and that a decrease in daily sleep has paralleled the increases in obesity and diabetes in the U.S. No molecular mechanism has been proposed that can adequately link sleep loss to glucose regulation. It is thought that wakefulness imposes an energetic stress on active cells, and that a purpose of sleep is to replenish energy stores (e.g. glycogen in astrocytes fuels neuronal activity and is depleted over the course of the day) and/or allow the repair of accumulated damage. In support of this, we have detected endoplasmic reticulum (ER) stress, which can reflect both energy depletion and molecular damage in the brains of mice subjected to sleep deprivation (SD). ER stress induces the unfolded protein response (UPR), which proceeds through an adaptive phase, characterized by the induction of chaperones such as BiP, and then a maladaptive phase characterized by the appearance of the proapoptotic transcription factor CHOP. In young mice subjected to acute SD, there is a clear induction of BiP, whereas in older mice, we detect a basal level of ER stress and find that even acute SD is sufficient to induce CHOP. Surprisingly, we find that the UPR is also induced in alpha and beta cells during SD. This is intriguing as these cell types play a direct role in glucose homeostasis (as producers of glucagon and insulin, respectively), and like neurons, have high energetic demands that are maximal during wakefulness. We hypothesize that chronic SD, in combination with other ER stressors such as aging or obesity induces the maladaptive phase of the UPR, leading to neuronal and endocrine dysfunction, cell loss, and detrimental effects on whole-body metabolism. Strikingly, deletion of CHOP in diabetic mice has been shown to spare functional beta cells, resulting in improved glucose homeostasis. Moreover, a class of small molecules can mimic the chaperone function of BiP and have been shown to alleviate ER stress in vivo. We will test the hypothesis that the UPR mediates metabolic consequences of SD by 1) measuring ER stress and the UPR in young and aged mice subjected to chronic SD and by 2) directly testing molecular chaperones as therapeutics. Understanding both the aging UPR and the pathogenesis of SD has the potential to lead to new therapeutic approaches in the treatment and prevention of diabetes and potentially many other disorders.
- Harold Riethman, PhD
"Single-Cell In Situ Analysis of Aging Using Telomere Probes and Discrete Subtelomeric Probe Sets"
Abstract:
Telomeres consists of stretches of (TTAGGG) repeat DNA at the ends of chromosomes with their associated proteins, and their dysfunction contributes to organismal aging. Telomere uncapping caused by critically short telomere DNA sequence induces senescence of somatic cells, which can disrupt normal tissues and, in the case of somatic stem cell populations, prevent proper replenishment of rapidly dividing cellular lineages, both leading to aging phenotypes. Telomerase, the enzyme complex that normally adds (TTAGGG)n sequences to telomeres in a highly regulated fashion in germ cells and stem cells, is limiting in rapidly proliferating cell lineages, such as those in the immune system and intestinal mucosa; for example, short telomeres associated with human telomerase haploinsufficiency in Dyskeratosis congenita (DC) patients result in, among other phenotypes, bone marrow failure and increased susceptibility to a variety of cancers. These phenotypes have been shown to depend directly upon short telomere length rather than loss of telomerase activity; upon restoration of telomerase activity in aged mice, telomeres are lengthened and aging phenotypes are reversed. In addition to the inherited component of telomere length regulation and the well-characterized reduction of telomere length with age in humans, telomere attrition is accelerated by chronic exposures to a variety of environmental factors associated with elevated levels of inflammation and/or oxidative stress. For example, Telomere Rapid Deletion (TRD) events associated with oxidative stress and replication errors in and near telomeres can lead to telomere dysfunction, but these TRD events are missed by most current telomere length measurement methods, which focus on average telomere length in a sample.
We propose here to develop a comprehensive set of discrete subtelomeric probes for mouse and human chromosomes and apply them, in combination with probes for the universal (TTAGGG)n sequence present at both mouse and human telomeres, to in situ analysis of aging in cells and tissues from mice and humans. Dr. Riethman will develop the probe sets based upon his analysis of subtelomeric DNA in both species and will carry out the pilot in situ studies in human cells and tissues; Dr. Johnson will carry out the pilot in situ studies of the mouse probe sets. Both studies will utilize microscopy core facilities to assist with image analysis. These pilot studies will create preliminary data that will 1) enable and facilitate collaborative aging grants from Riethman and Johnson labs, and 2) establish a valuable local resource for many other labs at Penn that are studying telomere length regulation in aging.
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