IOA Pilot Research Grantees 2008
With the generous support from The Bingham Trust, the IOA is pleased to announce the following as awardees of a 2007-2008 Pilot Research Grant:
Aaron D. Gitler, PhD, School of Medicine
Olena Jacenko, PhD, School of Veterinary Medicine
Jesse M. Pines, MD, MBA, School of Medicine
Barbara Riegel, DNSc, RN, FAAN, FAHA, School of Nursing
Kathryn H. Schmitz, PhD, MPH, School of Medicine
James Shorter, PhD, School of Medicine
J. Paul Taylor, MD, PhD, School of Medicine
Li-San Wang, PhD, School of Medicine
For more information on the pilot studies being funded through IOA Pilot Research Grants, please see below. The IOA thanks the Bingham Trust for its generous support of this important research mechanism.
“A Yeast TDP-43-opathy Model”
Protein folding is critically important for all of life. Not surprisingly, problems in protein folding are the root cause of many of the most devastating diseases, which represent a major challenge as our population continues to age. These diseases, referred to collectively as protein misfolding disorders, include truly disastrous neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease) and the Frontal Temporal Dementias.
It is hypothesized that identifying and characterizing the specific disease proteins associated with these disorders will provide insight into the causes of these diseases and will aid in the development of biomarkers and therapeutic strategies. Recently, a misfolded form of a protein called TDP-43 was identified as potentially playing a major role in both ALS and a subset of the Frontal Temporal Dementias. The goal of this IOA Pilot is to study TDP-43, identifying and characterizing both its normal function as well as the cellular consequences of its misfolding. We are proposing a unique approach to this problem. We will use yeast cells to study TDP-43. These are the same yeast cells that bakers and brewers use to make bread and beer. Since protein folding is a universal challenge to all cells, from simple yeast to complicated neurons in our brain, we believe that the lessons we learn about how TDP-43 functions in yeast cells will be directly relevant to how it functions in human cells.
“Hypomorphic Perlecan Mice: A Model for Osteoarthritis and Osteonecrosis”
Numerous people are born each year with skeletal defects and many more acquire degenerative skeletal disease with age. Greater than 50% of the U.S. population 65 years or older are estimated to suffer from osteoarthritis (OA); another common degenerative joint disease is osteonecrosis (ON), which is a severe and debilitating form of OA resulting in bone destruction. With an increasing aged population, impact of these conditions compound over time as chronic pain limits activity and affects life quality of millions. To date, precise disease mechanisms underling OA and ON remain poorly defined. Treatment options are also limited due to ineffective ability of joint tissue (articular cartilage) to regenerate, combined with a lack of suitable animal models to test therapeutic interventions.
The goal of this proposal is to establish our genetically engineered mice that express low levels of perlecan, a molecule that is vital for skeletal development, as models for OA and ON. These mice model an inherited human skeletal disease (Schwartz-Jampel Syndrome), and exhibit acute OA and ON by 4 weeks after birth. We propose to elucidate molecular, biochemical, and biomechanical mechanisms of degenerative skeletal disease in these mice. Our ultimate goal is to use these mice for in vivo testing of therapies and preventative strategies for these conditions.
“The Impact of Emergency Department (ED) Crowding, ED Waiting Times, ED Length of Stay, and Hospital Occupancy on Survival for Older Adults”
Emergency department (ED) crowding is a nationwide crisis and is reported to be a major issue in greater than 90% of US EDs. Primary concerns with ED crowding are the potential for poor quality of care and the negative impact on patient care outcomes. Older adults may be the group at highest risk for poorer quality care and negative outcomes during times of ED crowding for many reasons including: 1) older adults frequently receive their care in EDs when they experience acute unexpected illnesses, 2) older adults frequently require extensive diagnostic testing and hospital admission, and 3) older adults often require more resources and care coordination. When an ED is in the high workload state of ED crowding where care demands exceed supply of both personnel and physical space, older adults may suffer because of delays in diagnosis, delays in critical treatments and delays inpatient plans of care. In addition, when the ED is holding high numbers of admitted patients because of high hospital occupancy, the overall capacity of the ED to evaluate new patients is reduced.
While we have demonstrated in preliminary studies that ED crowding is linked to poorer quality of care for pneumonia, no studies have demonstrated an association between ED crowding and mortality outcomes for older adults. The aim of this study is to test the impact of ED crowding measures at the level of the individual patient (ED waiting room time and ED length of stay) and at the level of the hospital (ED crowding and hospital occupancy) on risk-adjusted inpatient and 30-day, and 60-day mortality for almost 11,000 older adults (65 and older) admitted to two inner-city hospitals in Philadelphia (Hospital of the University of Pennsylvania and Pennsylvania Presbyterian Hospitals) over 3-years. We hypothesize that risk-adjusted survival for older adults will be poorer at high levels of hospital occupancy and ED crowding and that these effects may be mitigated by a patient-level exposure to prolonged ED waiting room time and ED length of stay. Measuring the impact of ED crowding on older adults is crucial. As government regulators make decisions on hospital performance measures and pay-for-performance, understanding which ED crowding factors impact outcomes for older adults may inform hospital-level planning and quality improvement. The goal of this study is to serve as preliminary data for a larger grant aimed at mitigating the impact of ED crowding on older adults.
“Symptom Recognition in Elders with Heart Failure”
Aging is associated with various sensory changes. Vision, hearing and perhaps taste become blunted as we age. We suspect that elders also may experience some decrements in the ability to detect symptoms such as shortness of breath, which is a common symptom of heart failure. Persons with heart failure need to monitor their early symptoms so that they can act on them before they get out of control. Thus, the ability to detect symptoms such as shortness of breath is important for self-care.
The aim of this study is to test the hypothesis that the ability to detect shortness of breath is poorer in elders than in younger patients with heart failure. We will compare two groups, those younger than age 65 and those 65 or older. First we will stimulate shortness of breath using a 6-minute walk test. Following the stimulus, the ability to detect shortness of breath will be compared to gold standard ratings of each person’s shortness of breath provided by trained research assistants. Accuracy of ratings—congruence between patient and research assistant ratings of shortness of breath—will be compare in older and younger heart failure patients. A secondary aim is to assess symptom interpretation by interview in a subset of older and younger patients to determine the meaning attributed to symptoms when they occur. This study will be conducted in Melbourne, Australia where the principal investigator will be doing a Fulbright scholarship early in 2008.
“Does adjuvant breast cancer treatment accelerate aging associated functional decline?: A PILOT Study”
There have been many exercise intervention studies conducted in breast cancer survivors. These studies have shown that exercise can improve strength and aerobic fitness and quality of life among breast cancer survivors. However, there has been variability in the effectiveness of these interventions, and there are many reasons to believe that exercise studies in breast cancer survivors have yet to show their maximal impact. One of these reasons is that the studies have included ALL breast cancer survivors, rather than targeting the subset of women who need an exercise intervention the most. Another reason is that these interventions may not have targeted the specific causes of strength and fitness declines experienced by some breast cancer survivors as a result of treatment. The purpose of this line of inquiry is to help us to answer 2 questions:
- To better understand the characteristics of women at greatest risk for reduced strength and fitness with breast cancer treatment
- To better understand the specific causes of reduced strength and fitness due to breast cancer treatment.
To answer these questions, our goal is to recruit women just after breast cancer surgery and have them complete a set of surveys and in person assessments. We will then ask them to return for the same assessments at the end of their breast cancer treatment, or 6-9 months later if surgery is their only treatment. Most women experience no clinically relevant changes in strength and fitness as a result of breast cancer treatment. However, research studies have shown that there is a subset of women for whom breast cancer treatment results in a significant and clinically meaningful decline in strength and fitness that is larger than would be expected based on living for the same period of time without having had cancer treatment. The goal of this research is to identify the pre-existing, diagnostic, and treatment related characteristics associated with these declines (so we can know who needs an intervention to restore fitness after treatment) and the body systems associated with these declines (so that we can know whether post treatment exercise interventions should focus more on building strength, building aerobic fitness, flexibility, or balance, or some combination of these factors).
“Elimination of alpha-synuclein amyloidogenesis and proteotoxicty using Hsp104”
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, afflicting ~1% of individuals over the age of 65. There is no cure for PD. PD results primarily from the selective death of the nerve cells in the brain that produce the neurotransmitter dopamine. Overwhelming evidence implicates a specific protein, a-synuclein, as a causative agent of PD. In PD, a-synuclein adopts an aberrant shape, which is not found in healthy individuals. In this IOA pilot, we will investigate how another protein, Hsp104, may antagonize the formation of this aberrantly shaped a-synuclein, and so prevent the onset of PD.
"Histone deacetylase 6, authophagy and age-related neurodegeneration"
Autophagy is a catabolic process for degrading and recycling cytoplasmic constituents in all cells. In the brain, autophagy plays a vital role in protecting against the deleterious consequences of accumulating aged, damaged proteins. In fact, it has been determined that a deficiency in autophagy leads to neurodegeneration. We recently identified histone deacetylase 6 (HDAC6) as a cytoplasmic enzyme that is essential for misfolded proteins to be degraded by autophagy. We hypothesize that HDAC6 plays a vital role in protecting age-related accumulation of misfolded protein in neurons. In the proposed project, we will use the model organism Drosophila melanogaster to determine 1) whether loss of HDAC6 leads to age-related neurodegeneration, and 2) whether HDAC6 is a component of the basic autophagy machinery.
“The role of G-quadruplexes in senescence through RecQ-dependent pathways”
G-quadruplexes (G4s) are stable DNA structures comprising stacks of G-quartets, which themselves comprise four hydrogen-bonded guanines. These structures are abundant in the telomeric regions of humans and many other species, and may be crucial for telomere maintenance; moreover, recent studies of the human genome showed gene promoter regions have a higher-than-expected G4 forming potential, suggesting a role in gene expression regulation.
The human RecQ family includes five DNA helicases which are important for telomere maintenance, and their RQC domains bind to G4 DNA. Deficiency in any one of three RecQ genes leads to a genetic disorder of premature aging or predisposition to cancer, for example Werner syndrome or Bloom syndrome. Thus, interactions of RecQ helicases with telomeric and non-telomeric G4s may play a role in telomere-related processes related to the biology of aging and cancer.
The goal of the project is to study the biological role of G-quadruplexes in gene expression regulated by the human RecQ helicases. First, we will develop new computational methods for predicting which parts of the genome can form G4s. Second, we will compare the gene expression profiles between primary fibroblast cell cultures from patients with the three RecQ associated genetic disorders to identify genes that have altered expression due to perturbation in G4 DNA. These studies should improve understanding of mechanisms underlying age-related diseases and cancer.