IOA Pilot Research Grantees 2011
Once again this year, thanks to the generous support of The Bingham Trust, the IOA was able to award 9 full Pilot Research Grants in support of aging and aging-related disease research. One pilot was co-sponsored by the Penn Center for Musculoskeletal Disorders and is denoted by an *. Congratulations to this year's awardees.
2011 Pilot Research Grant Awardees
This year's Pilot Research Grant Awardees are as follows:
Katherine Abbott, PhD, MGS, Penn School of Nursing
Benoit Giasson, PhD, Penn School of Medicine
Kurt Hankenson, PhD, Penn School of Veterinary Medicine
Olena Jacenko, PhD, Penn School Veterinary Medicine *
Sangwon Kim, PhD, Penn School of Medicine
Jun Mao, MD, MSCE, Penn School of Medicine
Eileen Shore, PhD, Penn School of Medicine
Neal Sondheimer, MD, PhD, Penn School of Medicine
Wei Tong, PhD, Penn School of Medicine
- Katherine Abbott, PhD
"Social networks in long-term care: Enhancing existing approaches to measurement: A pilot study"
Recent studies have highlighted the importance of social networks for individuals’ health. Limited evidence, however, exists for an important subset of the population that are very dependent on social interactions for their emotional and physical well-being: older adults in long-term care settings. Obtaining reliable and valid information of the interaction between individuals and their social environment is therefore expected to become an important aspect to our country’s response to the increasing number and diversity of older adults in need of long-term care (LTC) services. The proposed pilot study is designed to test the feasibility of capturing social network information using enhanced methods that specifically address the complexities of the LTC and elder population. The three aims of this study are to: (1) develop social network interview guides that will capture recent social interactions of elders in LTC as reported by the elder, paid LTC staff, and informal caregivers; (2) pretest and assess the feasibility of administering the social network interview guides; and, (3) assess the consistency of resident reports of social interactions. The results will be used to assess and plan for needs vital to the success of an R01 application that will be submitted in October 2010.
- Benoit Giasson, PhD
"Characterization of LRRK2 kinase activity and mutants thereof causal of Parkinson's disease"
Parkinson's disease is the most common movement disorder, affecting over one million people in North America alone. For most patients the cause of Parkinson disease is still unclear. However, several specific genetic defects have been identified for many (~10%) patients. Recently, mutations in a gene termed leucine-rich repeat kinase 2 (LRRK2) were identified as the most common known cause of Parkinson's disease. Nevertheless, the function and specificities of this gene product and the effects of specific disease-causing mutations on these properties are still largely unknown. One of the goals of this project is to determine the effects of divalent metal ion, such as manganese that was suggested an environmental risk factor, on the ability of leucine-rich repeat kinase 2 to modify protein targets. In addition, a screen will be conducted to identify specific protein targets modified by leucine-rich repeat kinase 2. This project also will explore the hypothesis that some disease-causing mutations in leucine-rich repeat kinase 2 may alter the protein target specificity. This grant will result in critical findings that will provide important insights into the biological function of leucine-rich repeat kinase 2 and its participation in the development of Parkinson's disease. In addition, these findings may further compel efforts to identify therapeutic agents that can alter the activity of leucine-rich repeat kinase 2 as a possible treatment for Parkinson's disease.
- Kurt Hankenson, PhD
"Notch signaling in bone regeneration"
Bone regeneration is defective in geriatric patients. While decreased efficiency of bone healing is likely multi-factorial, there is a generalized decrease in bone formation with aging that is in part associated with a decrease in the number of osteoblast precursor mesenchymal progenitors (mesenchymal stem cells-MSC). A healing deficit is also observed in other tissues, such as muscle, with age. One explanation for decreased muscle healing with aging is a well-recognized deficiency in Notch signaling. Notch signaling is a cell-to-cell growth factor pathway. Notch signaling is also active during bone regeneration; however, there has not been a report of decreased Notch signaling in bone associated with age nor associating defects in healing with alterations in Notch. */We hypothesize that Notch signaling is reduced in aged MSC. /*This contributes to a decrease in MSC number and function and defective bone regeneration observed with aging. By extension, we hypothesize that activating Notch signaling will promote bone regeneration.
This project will seek to understand the cause of underlying age-related changes including reduced bone mass, diminshed blood formation, and deficient immune function leading to bone cancer.
- Sangwon Kim, PhD
"The role of IPMK in mTOR pathway and autophagy"
Aging is a complex process regulated by various molecular pathways and biochemical events. A flurry of remarkable research activities has recently expanded our understanding of the molecular and cellular events influencing aging/longevity. However our understanding of this multifaceted process is far from complete. A growing body of evidence indicates a strong link between the reduction of autophagic functionality and aging. Autophagy plays a key role in cellular housekeeping by removing damaged organelles. During aging, the efficiency of autophagic degradation declines and intracellular waste products accumulate. In this context the preservation of a proper autophagic response is of paramount importance to the maintenance of cellular processes in the aging cell. Nutrients' availability is the most physiological key regulator of autophagy. Moreover, a recent study unveiled that a key molecular component for nutrient sensing, Target of Rapamycin (TOR) is one of the major regulators of autophagy. In our recent genetic screen using yeast, we identified that one of the enzymes involved in inositol metabolism, inositol polyphosphate multikinase (IPMK) is required for mammalian TOR (mTOR) signaling pathway functionality and potentially autophagy. This observation led us to hypothesize that IPMK is a novel regulator of the aging process and plays a key role in cellular senescence. In this proposal research, we will attempt to establish a novel link between a relatively uncharacterized protein, IPMK and cellular senescence and to identify the biochemical mechanism behind this interaction. Therefore, this research is likely to speed the development of medical interventions that slow aging and extend the duration of healthy adult life.
- Jun Mao, MD, MSCE
"Telomere maintenance and musculoskeletal aging in breast cancer survivors"
Early screening coupled with advanced technology has increased survival among women with breast cancer; thus, an understanding of aging issues in the context of existing cancer therapies is important to improve the health and wellbeing for millions of breast cancer survivors. Aromatase inhibitors (AIs) are a standard hormonal treatment, blocking the conversion from androgen to estrogen. While AIs help prevent breast cancer recurrence via estrogen deprivation, this process may result in accelerated musculoskeletal aging manifested as arthralgia (joint pain), decreased bone mineral density, and fractures. Emerging research also suggests that estrogen is necessary for telomere maintenance and helps prevent cellular aging. Thus, we seek to perform an epidemiology study to characterize the relationship between patient reported AI-associated arthralgia (AIAA) and telomere length in peripheral blood. We hypothesize that while AI-associated arthralgia (AIAA) in breast cancer survivors is the clinical presentation of an accelerated musculoskeletal aging process, telomere shortening in peripheral blood leukocytes is the molecular signature. An understanding of the relationship between hormone therapy and telomere maintenance is a necessary first step in indentifying those patients at risk for accelerated cellular aging, and will help develop interventions to promote healthy aging and overall wellbeing in this population.
- Eileen Shore, PhD
"Modulation of progenitor cell differentiation through BMP signaling"
Aging of bone is characterized by changes that decrease bone strength and predispose bone to damage. As a consequence, common clinical challenges in the elderly are osteoporosis and the associated high risk of fracture. Rare genetic disorders, though directly impacting relatively small segments of the population, can provide critical insight into fundamental cellular mechanisms such as bone quality. One such disease, fibrodysplasia ossificans progressiva (FOP) is characterized by congenital skeletal malformations and progressive extra-skeletal (heterotopic) endochondral ossification, and is caused by mutation of the ACVR1/ALK2 protein, a specific cellular receptor. Our studies have suggested that the mutated ACVR1 receptors raise the set point of cells to be more sensitive to interactions with molecular and mechanical inducers and modulators of bone and cartilage cell formation. In our proposed series of investigations, we will examine cell growth characteristics of progenitor/stem cells with the normal and mutant ACVR1 receptor and define the cell fate decisions that are altered in response to these signals.
- Neal Sondheimer, MD, PhD
"The effect of aging on mitochondrial heteroplasmy and mitochondrial dysfunction"
The mitochondria provide much of the energy for our cells, and are unique because of the use of a small, maternally-inherited genome. It has been known for some time that mitochondrial function declines in tissues from elderly patients, but the reason for this decline is unclear. Some changes in mitochondrial DNA have been previously observed, including an increase in copies of this DNA that are missing information. In this study, we will attempt to identify the rate at which mutations emerge in mitochondrial DNA across the human lifespan. We will also correlate the emergence of age-related mutations with loss of mitochondrial function, by isolating mitochondrial DNA sequences from the elderly and determining its influence on the capacity of mitochondria to generate power. This research will help us to determine whether approaches designed to improve the integrity of the mitochondrial DNA could ameliorate some of the effects of aging.
- Wei Tong, PhD
"Aging of hematopoietic stem cells"
Blood cells are continually produced from the hematopoietic stem cells (HSCs) that reside in the bone marrow. Throughout the life of the organism, the HSC reservoir sustains blood formation. Although HSCs are endowed with self-renewal capability, their life-span is limited and the HSC pool can be exhausted following regenerative stress. However, the mechanisms for HSC aging are not well understood. The adaptor protein Lnk is an important regulator of HSC homeostasis by limiting self-renewal. Mice lacking Lnk (Lnk-/-) harbor an expanded HSC pool during postnatal development. Specifically, we demonstrated that young Lnk-/- HSCs exhibit enhanced self-renewal with superior repopulation abilities in serial transplantation assays. Furthermore, Lnk-/- mice show alterations in the HSC compartment during aging, which is accompanied by a marked increase in the peripheral blood count. We aim to investigate molecular mechanisms by which Lnk affects HSC self-renewal during aging. The research proposed here aims to achieve a mechanistic understanding of how signaling molecules important for HSC expansion and self-renewal regulate HSC aging. These studies could provide new insights into stem cell aging and facilitate clinical applications to stem cell therapy in the treatment of aging- related diseases.