The objective of the Pilot/Exploratory Studies Core (PESC) of the Duke Pepper OAIC is to conduct pilot studies to acquire information needed to design more definitive, larger studies to understand and modify multiple pathways of functional decline. The specific aims are to generate novel ideas for pilots studies; to solicit, select and provide research funding for the highest quality pilot studies; to
facilitate successful completion of the pilot studies and their development into externally funded, larger grants; to attract promising junior investigators to aging research; to foster multi-disciplinary/translational research; to educate developing investigators about the logistics and science of pilot studies via an innovative Pilot Studies Workshop, to share our expertise with the Pilot Studies Workshop to other Pepper OAlCs in collaboration with the OAIC Coordinating Center at Wake
Forest University, to use small exploratory pilot monies as a rapid response mechanism to take advantage of cutting edge areas; and to contribute to other important NIA pilot mechanisms. The PESC solicits and selects high quality pilot studies from across Duke University Medical Center using rigorous external peer review. The PESC monitors study progress and assists in the development of
larger grant proposals from pilot study findings. Three pilot studies are proposed in the first two years. PES-1 examines the role of skeletal muscle changes to different training regimens and evaluates the contribution of these changes to functional performance in the older adults. PES-2 addresses the problem of severe sepsis and multiple organ dysfunction syndrome by determining the effects of exercise on organ and immune cell mitochondrial biogenesis during sepsis. PES-3 addresses how the functional trajectory of patients with an index disease (diabetes for this study) is worsened by the presence of co-existing medical conditions (cognitive impairment). The PESC impacts public health by performing studies that develop knowledge to maintain or restore independence in older Americans.
The Duke Older Americans Independence Center (OAIC) is structured to (1) enhance and support research and (2) research career development in aging research through its Core resources. The central theme of our OAIC is to understand and modify the multiple pathways of functional decline. The OAIC is based in the Duke Center for the Study of Aging and Human Development, an all-university program with strong multidisciplinary affiliated programs such as the Durham VA GRECC, the Hartford Center of Excellence, the Duke Institute for Genomic Sciences and Policy, the Duke Translational Medicine Institute, the Duke Center for Living, and the Stedman Nutrition and Metabolism Center. This rich mileu includes 130 faculty as Senior Fellows of the Aging Center and over 25 million dollars of research germane to the goals of the OAIC. The Duke OAIC will support two resource cores which have evolved from prior OAIC support: (1) an Analysis Core and (2) a Biological Studies Core. Five externally funded NIH/ VA grants, with study aims and study populations that integrate into our thematic focus, will receive support from these cores; with new specific research aims relevant to our Center. The Research Career Development Core and the Pilot/Exploratory Studies Core will facilitate career development with established post-doctoral Research and Geriatric Training Programs. During the first year, three pilot projects, one development project from each research core, and three junior faculty will be supported. Subsequent support for career development and pilot projects will be selected on a competitive basis using criteria clearly defined in the OAIC guidelines. A Leadership/ Administrative Core will direct and coordinate OAIC activities to ensure continued integration of center activities.
The Leadership/Administrative Core (LAC) will have responsibility for the overall direction and operation of the Older Americans Independence Center. Our proposed center consists of a Research Career Development Core, a Pilot/Exploratory Studies Core, and two Research Cores, the Analysis Core and the Biological Studies Core; all under the direction ofthe Leadership/Administrative Core. Each of the cores will have an internal management and decision-making structure and will be granted considerable autonomy for internal research and financial operations. The primary coordinating unit will be the Internal Operating Committee as the central decision making body to successfully lead the new Center. This approach will have maximal impact on fostering geriatrics research and training in a dynamic, multidisciplinary environment. The LAC will provide the leadership necessary to harness and direct the creative energy of this complex research activity. The Core will have input from, and interaction with, key members of other units of the Medical Center, the
University, and the Durham VA and will rely on two panels. Independent Review Panel and External Advisory Committee for expertise and direction in selection of future projects, pilots and junior faculty awardees. The specific goals ofthe LAC are: (1) To assure overall coordination, integration, and administration of the Duke Pepper OAIC; (2) To assure integration with other affiliated programs, e.g..
Center for the Study of Aging, the Hartford Center of Excellence, Durham VA Geriatric Research, Education and Clinical Center, Duke Translational Medicine Institute, Alzheimer's Disease Research Center, Aging Center T-32 Post-Doctoral Training program, and others.; (3) To assure efficient and appropriate use of core facilities by investigators and programs; (4) To plan and develop funding
strategies for cores and support of projects; and (5) To plan and coordinate future core activities and integrate Duke Pepper OAIC activities with new programs established at Duke Medical Center.
The goal of the Research Career Development Core (RCD Core) is to recruit, train, mentor, and develop future research leaders with skills in translational research and clinical investigation directed at exploring approaches to understand and modify multiple pathways of functional decline. Previous experience with our OAlC-supported Research Development Core has taught us that we must aggressively
recruit, select, mentor and train promising junior faculty to enter the field of aging research. Promising scientists will be recruited to develop and/or expand their investigative skills with an emphasis on translating basic research findings into clinical studies or, taking clinical research findings and posing new basic research questions. RCDC Scholars will take courses tailored to their specific career needs, receive mentoring from their senior faculty team, and receive leadership training to prepare them for key positions in geriatrics and gerontology. Our mentoring plan is designed to motivate clinical investigators to explore basic research principles and basic scientists to interface with clinical researchers. The RCD Core will ensure that
its awardees take advantage of other OAIC research cores and other experienced investigators at Duke University Medical Center. RCD Core awardees will participate in OAIC seminars and conferences where interdisciplinary investigators discuss their work In this milieu ideas for collaborations are started and discussed, resulting in new projects and lines of inquiry. For each junior faculty member chosen as an RCDC Scholar the Duke Pepper OAlC's intended outcome is to prepare and support them to become independent investigators doing aging research. After two to three years of support, success for each RCDC Scholar will be measured by their ability to secure research career development support or independent investigator- Initiated extramural funding. RCD Core Project Leader, Kenneth Lyles, MD will work
especially closely with Pilot /Exploratory Core Studies Core Project Leader, Kenneth Schmader, MD, to maximize the use of our Core's resources to help prepare our awardees so they have the requisite skills as well as pilot data to successfully complete for career-development awards, and when appropriate investigator-initiated funding. As occurred over the previous 19 years, with previous Pepper GRTC and OAIC support, the RCD Core will produce talented, well-trained investigators to help lead the next generation of scientists in the field of aging directed at positively clinical, translational or basic research that focuses on exploring multiple approaches to understanding and modifying multiple pathways of functional decline.
The overall goal of the OAIC program is to increase scientific knowledge that will lead to effective ways to maintain or restore independence in older Americans. Innovative and appropriate analysis and data management methods are an important and necessary component to the scientific endeavor. A variety of designs, variables, hypotheses, and analyses will be explored, all with the common theme of
'Pathways to Disability'. An analysis core (AC) is proposed with 3 goals - (1) to provide an appropriate data management and analytic resources to the faculty, pilots, and projects in the Pepper Center, (2) to provide a resource in the measurement of physical performance, function, cognition, design and
analysis so that appropriate measures will be employed using appropriately designed and analyzed experiments with appropriate conclusions, and (3) to develop innovative biostatistical analytic methodologies. To accomplish these goals, personnel with expertise and experience in data management, analysis, and measurement will direct activities in support ofthe overall Pepper. Both standard and innovative data management methods are proposed and employed, including
standardization of analytic methods across studies and construction of data bases with common measures and variables. In addition to provision of technical analytic and data management support, the core will provide consultation, training and research support to the faculty ofthe Pepper Center.
The core will also pursue methodologic goals of interest to statisticians and basic scientists. In particular, in order to develop valid and reproducible models ofthe relationship between biomarkers and function, several analytic considerations must be considered, including Type-1 error control for multiple testing, data aggregation, and measurement of change over time in several domains simultaneously. Working closely with the Biological Studies Core (RC2), we will focus on methods for
examining trajectories of change in the biological and clinical expression of function, establish temporal ordering in these estimates, assessment of constancy of these relationships across studies, developing appropriate error structures for analysis given complex sampling schemes.
The purpose of the Biological Studies Core (RC2) facility is to provide a centralized resource for biomarker analyses in support of Duke Pepper OAIC projects to evaluate biomarker profiles as mediators and predictors of function and functional decline. This Core will provide a comprehensive laboratory facility for assays of cellular, molecular, biochemical and metabolomic factors related to aging and functional decline, inflammation and joint tissue metabolism.. The proposed Core Facility will serve in these capacities and will provide biomarker analyses to three large new externally funded studies in human cohorts to validate associations, discovered through the Duke Pepper OAIC in the previous 5 years, of physical function and functional decline with biomarkers, and to expand, enhance and refine knowledge related to these biomarkers as potential mediators and predictors of function. These three cohorts will afford the opportunity to: 1) assess the strength of the prognostic capability of the biomarkers for predicting risk of functional decline or mortality over the subsequent 1-3 years; 2) assess concurrent change in biomarkers and function in a community sample with acquisition of baseline and 24-month longitudinal samples; 3) assess both concurrent change in biomarkers and functional status and the impact of an exercise intervention on biochemical and metabolic markers as well as physical function. The Core Facility will also initially support
one Developmental Project to advance the understanding of metabolic function and aging. This project will focus on developing a targeted mass spectroscopic analytic method for acylglycines in urine and will evaluate concurrent change in this new marker and metabolic health and insulin resistance with a clinical trial intervention of glycine supplementation in animals. This Core will also continue to serve as a resource for the training of investigators on principles and methods of biomarker analyses. These biomarker studies are expected to provide further insights into the molecular pathophysiology of aging to inform potential new strategies for intervention and modification of functional decline. The overall approach will continue to be one of a 'Collaboratory' in which multiple excellent clinical studies will contribute subsets of samples for biomarker analyses by the Duke Pepper OAIC Biological Studies Core, and statistical analysis of results by the Duke Pepper OAIC Analysis Core, to address, jointly and severally, the overarching Duke Pepper OAIC theme of exploring approaches to understand and modify multiple pathways of functional decline, and to translate noteworthy findings into disseminated knowledge through publications and advances in health.
