The Center on Aging Steering Committee received 17 pilot grant submissions in 2014. We had a difficult challenge selecting from this group of meritorious projects! We are pleased to announce the following recipients of 2014-15 Pilot Grant funding:
1. Kara B. Dassel, Ph.D.
“The Influence of Disease Type on End-of-Life Care Preferences”
Preparation for end-of-life (EOL) care is a significant area of interest for both clinicians and researchers in light of the growing older adult population. EOL care preferences have been extensively studied in relation to global “terminal illnesses”, typically cancer, but there is very little literature that has explored EOL wishes with terminal neurodegenerative disorders such as Alzheimer’s disease (AD). The influence of psychosocial factors such as death anxiety, religiosity, and demographic variables such as age, gender, and education level have been explored extensively in the EOL and palliative care literature, but there has been very little investigation of the influence that multi-dimensional health variables have on EOL care preferences.
Furthermore, examination of EOL care preferences in relation to different specific disease trajectories has yet to be conducted. Therefore, the purpose of the current study is to explore EOL care preferences in relation to three different hypothetical progressive disease scenarios (i.e., pancreatic cancer, Alzheimer’s disease, and congestive heart failure) and to examine the influence of participant health status in the areas of mood, health-related quality of life, frailty, comorbid chronic disease, and functional status on these care preferences. Participants age 40 and older will be recruited from a large volunteer research participant database and will complete a series of demographic and health questionnaires. In addition, participants will be asked to select their anticipated preferences for EOL care based on three hypothetical disease models. EOL care preferences for each hypothetical disease model and the influence of health and other demographic variables on EOL preferences will be analyzed using linear mixed effects regression models. The primary objective of the current pilot study is to obtain data that will aid in the future development of a disease-specific EOL preference measure for persons with Alzheimer’s disease and to use this tool to study longitudinal change in EOL preferences in caregiving spousal dyads.
2. Heidi Hanson, Ph.D
“The Airderly Study: Air Quality, health and Mortality in the Medicare Population”
Ambient air pollution is one of the greatest environmental threats to human health, with approximately 3.7 million, or 6%, of deaths globally per year contributed to the noxious problem. A recent statement from the American Heart Association called for a better definition of susceptible individuals or vulnerable populations. This study uses a comprehensive population-based resource, the Utah Population Database (UPDB) linked to Centers for Medicare and Medicaid Services (CMS) records from 1992 - 2009 to study the effects of ambient air pollution on morbidity and mortality in the 65+ population. We examine the relationship between air pollution and cardiovascular and pulmonary morbidity and mortality for socioeconomically disadvantaged individuals, individuals with preexisting conditions, and individuals with chronic comorbid conditions in this population. This study will significantly improve our understanding of the heterogeneous effects of increased levels of ambient air pollution in the population over age 65.
3. J. David Symons, Ph.D.
“Links among autophagy, mitophagy, and nitric oxide bioavailability in aging”
Autophagy or "self-eating" is a cellular quality-control process wherein damaged proteins and organelles are recycled to ultimately provide new nutrients and energy. This process has been examined in numerous tissues (e.g., liver, heart) and, in general, autophagy is supressed in the context of healthy aging. One study exists concerning autophagy in the vasculature, and supports data from other tissues i.e., autophagy is less robust in arteries from old vs. young mice. Mitochondria produce ATP via oxidative phosphorylation and, as such, are crucial to cell viability. Mitochondria also play the role of signaling organelles by producing reactive oxygen species. During the process of aging, "dysfunctional" mitochondria become producers of excessive reactive oxygen species (ROS) which can limit nitric oxide (NO) bioavailability and contribute to arterial dysfunction. The process of mitochondrial autophagy i.e., mitophagy, is a recently discovered cellular defense mechanism designed to recycle / degrade dysfunctional mitochondria. We will test the overall hypothesis that suppressed vascular autophagy during the aging process leads to: (i) reduced endothelial cell (EC) mitophagy; (ii) increased ROS/reactive nitrogen species generation; (iii) reduced eNOS phosphorylation and NO bioavailability; and (iv) endothelial dysfunction. In Aim 1 we will determine the mechanisms by which suppressed autophagy impairs stimulated endothelial cell(EC), nitric oxide bioavailability in vitro. To do so, aortic ECs isolated from old and young mice will be studied under basal (static, no shear stress) and stimulated (20 dyn/cm2 shear stress) conditions. We hypothesize that when vascular autophagy and mitophagy are suppressed, mitochondrial function is impaired, ROS/RN generation exceeds the cellular antioxidant defense mechanisms to an extent that eNOS enzyme function is disrupted. In Aim 2 we will determine the molecular mechanisms whereby suppressed autophagy impairs stimulated vascular NO bioavailability in vivo. Arteries from young and old mice will be studied at rest and 30-min post 60-min of treadmill-running. We expect exercise-induced increases in NO bioavailability are limited in vessels from old vs. young mice, secondary to decreased autophagy/mitophagy and exaggerated ROS/RNS.
4. Craig Teerlink, Ph.D.
“Sequencing analysis of high risk pedigrees to identify bone density predisposition”
Prior evidence suggests the presence of strong genetic predisposition to osteoporosis, but the genetic basis of the disease is not fully specified. Because osteoporosis is treatable and even preventable, the identification of genetic variants can enhance disease prediction, screening and treatment. The central aim of the proposed research is to identify predisposing genetic factors for osteoporosis using the well-established high risk pedigree design, which is practical, efficient and powerful for investigating rare variation. We previously created a large resource of extended high-risk osteoporosis pedigrees using a genealogy of the state of Utah linked to medical data for the largest Utah health care provider. The pedigree resource contains 276 multi-generational osteoporosis pedigrees with an average of 14 sampled individuals per pedigree. All sampled individuals were tested for bone mineral density (BMD) at the spine and pelvis. The distribution of normalized BMD at both sites was calculated and severe cases were defined as those in the lowest 5% of the distribution of either site. We propose to identify 2 cases from the 6 most informative high-risk osteoporosis pedigrees with 2 or more sampled cases with normalized BMD score < -2.5 who are distantly related to each other (at least first-cousins). This design will provide us with an informative set of osteoporosis cases most likely to be segregating a predisposition variant. The genetic distance between each pair provides evidence of identity by descent genetic sharing, which serves as an efficient filter for deleterious candidate variants. We will perform whole genome sequencing of the 12 most severe distantly related cases. The sampling strategy is designed to identify predisposition variants that occur in both sequenced severe cases in the same pedigree. This project is intended to leverage the cost effective availability of high-throughput genomic sequence data and provides an opportunity to interrogate a high-risk familial set of osteoporosis families. It is expected that the combination of this analysis approach and this particular set of cases will provide an optimal means to identify specific variants that contribute to this disease. A successful outcome will provide opportunities to expand the project with future funding.
5. Peter J. West, Ph.D.
“5-HT6 localization and function: a prototype target for cognitive therapies”
Treatments that attenuate memory deficits will improve quality of life and diminish the heavy financial and emotional burden of neurological disease. New treatments are needed because currently available therapies are few in number, mechanistically homogenous, and only marginally effective. One approach for future therapy discovery is to first obtain a mechanistic understanding of existing treatments, including those in development, in order to “fine-tune” their targeted effects or discover new therapeutic approaches. One such class of promising treatments currently in development are serotonin (5-HT) 5-HT6 receptor antagonists. However, gaps in our knowledge of 5-HT6 receptor localization and function preclude a mechanistic understanding of their antagonists’ therapeutic effects. This proposal will dissect 5-HT6 receptor localization and physiology, as well as the mechanisms of action of their antagonists', with unprecedented precision. This objective will be accomplished by utilizing transgenic mice expressing a 5-HT6 EGFP reporter to test the hypothesis that 5-HT6 receptor antagonists decrease inhibitory synaptic transmission by reducing the excitability of discrete interneuron subtypes in the dentate gyrus (DG). The specific aims of this proposal are as follows: Specific Aim 1: Determine if 5-HT6 receptors are located on discrete inhibitory interneurons in the DG. We will immunostain tissue from transgenic mice that express a 5-HT6 receptor EGFP reporter. Immunostaining with markers for interneuron subtypes will reveal cell-type specific localization of 5-HT6 receptors in the DG with unprecedented precision. Specific Aim 2: Determine if 5-HT6 receptor antagonists decrease interneuron excitability in the DG. We will use whole-cell patch-clamp technique in acute brain slices to record from htr6-EGFP+ inhibitory interneurons and determine how 5-HT6 receptor antagonists affect excitability. Results from these studies will provide a blueprint for the memory enhancing effects of 5-HT6 receptor antagonists and direct the discovery of new therapeutic approaches for memory impairment in aging. Furthermore, these experiments will set the stage for future studies that will examine how 5-HT6 receptor expression is remodeled in disease such as epilepsy, Down syndrome, and Alzheimer’s disease.