Institute on Aging Pilot Research Grantees 2014
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.
2014 Pilot Research Grant Awardees
This year's Pilot Research Grant Awardees are as follows:
Jaimo Ahn and Kurt Hankenson, Perelman School of Medicine and Penn School of Veterinary Medicine
Brendan G. Carr and Nabila Dahodwala, Perelman School of Medicine
Edward B. Lee, Perelman School of Medicine
Zissimos Mourelatos and Marc A. Dichter, Perelman School of Medicine
- Jaimo Ahn, MD, PhD
"The Role of COX-2 in Aged Fracture Healing and Implications for Therapeutics"
Fragility fractures in the elderly are already a substantial source of morbidity and mortality to our aging population. With increased longevity, this is becoming a greater problem and burden for individuals, families, and society as a whole. As well, the ability to heal fractures decreases with age, whereas an eighteen year-old may heal a fracture in several weeks, an eighty year-old may take several months to heal the same fracture.
Many biological pathways can affect fracture healing. However, there are few that are well-characterized to be involved in aging and fracture healing in humans and for which we already have potential therapeutic interventions. The cyclooxygenase 2 (COX-2) pathway is one such pathway. Therefore, we propose to examine the role of COX-2 in a validated geriatric mouse fracture model and to determine whether therapeutic delivery of the COX-2 gene can enhance geriatric fracture healing.
The results of our proposal will lead to 1) a better understanding of key mechanism (COX-2) implicated in human aged fracture healing that is mimicked in a mouse model and 2) characterization of the causal relationship between that pathway and aged fracture healing. Our research will provide the basis for therapeutically manipulating the COX-2 pathway in geriatric fractures to improve fracture healing - thereby improving the ability of physicians to provide better fracture care for our geriatric patients.
- Brendan G. Carr, MD, MS
Nabila Dahodwala, MD, MS
"Improving Care for Injured Older Adults"
Injury is a major cause of death, disability, and healthcare utilization in the US. Trauma is the fourth leading cause of death in Americans aged 55-64 and the seventh leading cause for adults over the age of 65; falls are the primary driver of injury related death in this population. Rates of mortality and complications are higher for injured older adults than for similarly injured younger patients, and medical treatment of injured older adults is complicated. Multiple studies have described improved survival among younger adults treated at certified trauma centers as compared to non-trauma center hospitals. The benefit of trauma care for older adults, however, is substantially less clear, with the largest study to date demonstrating no benefit associated with care at a trauma center for adults older than 55 years. Clinical practice guidelines exist for the care of injured older adults, and the success of targeted interventions and multidisciplinary treatment teams have been described, but many questions remain about the structures and process of care that describe ideal trauma care for older adults. The broad objective of this study is to better understand the variability in outcomes that exists for injured older adults and to identify structures and processes that might contribute to improved outcomes in this population. We will accomplish this with a mixed-methods approach separated into two discrete aims. First, we will use trauma registry data for the state of Pennsylvania to examine the association between in-hospital death and age, as well as compare odds of death across hospitals, looking for the marginal benefit of trauma center care and examining the variability in outcomes between and within hospitals. Next, we will gather qualitative data from semi-structured interviews with patients, families, and community, prehospital, emergency department, and hospital providers to identify structures and processes that may lead to improved outcomes for older adult trauma patients. The pilot data obtained from these two aims will allow us to submit a larger proposal to develop a cohort of geriatric trauma centers in Pennsylvania and test their impact on injury outcomes for older adults.
- Edward B. Lee, MD, PhD
"Cytoplasmic Sequestration of RNA by Abnormal TDP-43"
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized pathologically by the presence of neuronal cytoplasmic TDP-43 protein aggregates. TDP-43 is an RNA-binding protein and under normal conditions is nearly exclusively nuclear. However, various stressors cause a redistribution of TDP-43 from the nucleus into the cytoplasm in relatively insoluble foci called stress granules (SGs). SGs sequester and protect vital RNAs during periods of stress and have been postulated to represent a precursor to neuronal cytoplasmic inclusions (NCIs). NCIs have been hypothesized to be toxic through an abnormal gain-of-function, and TDP-43 toxicity in a variety of models is linked to its ability to bind to RNA. Thus, I hypothesize that sequestration of vital RNAs within NCIs contributes to neurodegeneration. Within the nucleus, TDP-43 binds to predominantly intronic RNA to regulate splicing. The cytoplasmic RNA targets of TDP-43 must be a unique set of RNAs but are currently unknown. I propose methods to identify RNAs bound to cytoplasmic TDP-43 in stressed neuronal cultures to better understand the composition of TDP-43-positive SGs. I further propose biochemically isolating and sequencing RNAs bound to pathologic TDP-43 in human brains. These experiments will provide pilot data which will serve as the basis for further extramural funding and will address hypotheses about how SGs and RNA sequestration contribute to the pathogenesis of ALS and FTLD.
- Zissimos Mourelatos, MD
Marc A. Dichter, MD, PhD
"RNA Binding Proteins That Cause ALS and FTLD Regulate Synaptic Activities: Implications for Neurodegeneration"
Amyotrophic lateral sclerosis (ALS) is the most common human motor neuron degenerative disease with a fatal outcome and without a cure. Approximately 20% of ALS patients also develop frontotemporal lobar degeneration (FTLD), characterized by dementia due to degeneration of cortical and subcortical neurons. Recent studies have shown that RNA binding proteins (RBPs) are at the heart of ALS and FTLD pathogenesis, implicating that dysregulation of RNA pathways leads to neuronal toxicity that causes disease. Dominant mutations in genes coding for four hnRNPs (TAR RNA/DNA binding protein of 43 kDa, -TDP-43, TARDBP-; Fused in Sarcoma/Translocated in Liposarcoma, -FUS/TLS, FUS-; TBP-associated factor of RNA Polymerase II of 68-KD/15, -TAF68, TAF15-; and Ewing sarcoma breakpoint region 1, -EWSR1, EWS-) are found in familial and sporadic cases of ALS and FTLD. A number of recent studies have recapitulated TDP-43 and FUS mediated neurodegeneration in animal models and reveal that the RNA binding activity of TDP-43 and FUS is required for toxicity, suggesting that neurotoxicity is manifested by their impact on RNA targets.
We have recently identified the in vivo RNA targets for TAF15 and FUS in human and mouse neurons and we discovered that TAF15 and FUS regulate targets with synaptic activities and in particular glutamergic receptors. Given the large amount of altered regulation that each RBP mutation produces, it is possible that the ultimate neurotoxic effect will be quite complex and multifactorial. However, one unifying hypothesis (among several) is that altered regulation of the synaptic receptors for glutamate or other molecules related to these synapses, plays a significant functional role in the neurodegenerative process. This would be consistent with numerous studies relating to the pathophysiology of ALS that implicate dysregulation of glutamate in neurotoxicity. The research proposed in this application will attempt to determine the functional consequences on synaptic function and excitotoxicity (a direct form or injury to nerve cells due to excess excitatory drive) of FUS and TAF15 and of patient mutations causing ALS. This research program will open up new avenues of research into the mechanisms by which neurons are damaged by the mutated RBPs found in patients with ALS and FTLD. The proposal involves a new collaboration between two laboratories in separate departments that bring very different but very complementary approaches to attempts to understand the basic mechanisms underlying an important group of age-related neurodegenerative diseases.