DESCRIPTION (provided by applicant): 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 milieu 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 three resource cores which have evolved from prior OAIC support: (1) an Analysis Core, (2) a Biochemical Pathways Core, and a (3) Metabolomics Core. Several externally funded NIH, VA or industry-sponsored grants, with relevant study aims and study populations will receive support from these cores. New specific aims relevant to our Center theme will be added for each external project. Data from these studies (interventional and cohort) will be added to a common database that includes data from our prior funding periods. This extends our research capabilities and allows us to develop new ideas for investigation. The Research Career Development Core and the Pilot/Exploratory Studies Core will facilitate career development and enhancement of research capabilities with established post-doctoral Research and Geriatric Training Programs and participation in the Duke OAIC Research Seminar Series, the Data Integration Working Group, the Pilot Studies workshop, the Pepper Scholars program, and access as needed to a Functional Measurement Resource group. The cores are seamlessly integrated and work closely to develop young trainees and research projects by interactions from concept through completion of proposed work. During the first year, three pilot projects, two development projects, and three junior faculty will be supported. Subsequent support for career development, pilot projects, and development will be selected on a competitive basis using criteria clearly defined in the OAIC guidelines. A Leadership and Administrative Core will direct and coordinate OAIC activities to ensure continued integration of center activities.
PROJECT SUMMARY (See instructions): LAC The Leadership and 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 three Resource Cores; the Analysis Core, the Biochemical Pathways Core and the Metabolomics Core, all under the direction ofthe Leadership and Administrative Core. Each ofthe cores will have an internal management and decision-making structure while at the same time being highly integrated functionally with the other cores. 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 LAC administratively supports a Research Seminar Series, a Data Integration Working Group and a Functional Measurement Resource Panel. 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 Board 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 ofthe Duke Pepper OAIC including oversight of data safety and monitoring of studies; (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.
PROJECT SUMMARY (See instructions): PESC The objective ofthe Pilot/Exploratory Studies Core (PESC) ofthe 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 OAICs 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 investigates the molecular basis of sarcopenia. PES-2 explores innovative methods to phenotype urge urinary incontinence and to predict response to therapy. PES-3 will validate novel measures of vlsual function and real-world independence in older macular disease patients as a necessary step toward planning the Memory or Reasoning Enhanced Low Vision Rehabilitation trial. The PESC impacts public health by performing studies! that develop knowledge to maintain or restore independence in older Americans.
PROJECT SUMMARY (See instructions): RC1 The overall goal ofthe 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 are part ofthe Duke Pepper Center, all with the common theme of 'Pathways to Functional Decline'. Most of the studies assess the relationship of '-omic' markers to that pathway. An analysis core (AC) is proposed with 2 goals: (1) to provide an appropriate data management and analytic resources to the faculty, pilots, and projects in the Pepper Center, and (2) to develop innovative biostatistical analytic methodologies. The AC core is built to provide analytic support the junior and senior faculty across the range of designs and analytic issues inherent in the studies, including sociologists (latent variables), biostatisticians (design, longitudinal analysis, psychometrics), bioinformaticists (genetic and high dimensional data analysis), and statisticians for day-to-day monitoring of studies and data management. Data management will use secure web-based methods (REDCap), and methods from the Center on Human Genetics appropriate for managing high dimensional metabolomic, proteiomic, and genetic data. The panel of studies is constructed and managed so that standardized analytic methods and common measures across studies can be employed. Following our previous successes, the studies and methods lend themselves for use of meta-analytic techniques, allowing discovery of relationships, not possible in any small single study. In addition to provision of technical analytic and data management support, the core will provide consultation and training support to the faculty of the Pepper Center. The core will also pursue methodologic goals of interest to biostatisticians which address analytic issues encountered. In particular, in order to develop valid and reproducible models ofthe relationship between biomarkers and function, several analytic considerations must be developed, including Type-l error control for multiple testing, data aggregation, and measurement of change over time in several domains simultaneously. Working closely with the Biomarkers Cores (RC2 and RC3), we will focus on methods for examining trajectories of change in the biological and clinical variables, establish temporal ordering, assess mediation and moderation pathways, assess the constancy of the relationships across studies, and develop appropriate methods for complex error structures which result from complex sampling designs.
PROJECT SUMMARY (See instructions): RCDC The goal of the Research Career Development Core (RCDC) is to recruit, mentor and train future aging research leaders with skills in translational research and clinical Investigation focused on the Duke Pepper OAIC theme "to understand and modify multiple pathways of functional decline". Promising early investigators 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 a team of researchers with topic and/or aging research methodology expertise, and receive leadership training to prepare them for key positions in geriatrics and gerontology. Individual career development plans are created and regularly reviewed to ensure continued professional development. Our mentoring plan is designed to motivate clinical investigators to explore basic research principles and basic scientists to interface with clinical researchers. 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. The RCDC will ensure that its awardees utilize resources from other OAIC research cores when appropriate, and that awardees present their findings in the Data Integration Working Group to optimize data integration across the Pepper Center. For each early investigator 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 completion of proposed research, publications, and ability to secure research career development or independent investigator-initiated extramural funding. RCD Core Project Leaders, Kenneth Lyles, MD and Cathleen Colon-Emeric, MD, MHS, 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 and pilot data to successfully complete for new funding. Over the previous 19 years the RCDC has produced talented, well-trained investigators to help lead the next generation of scientists in clinical, translational or basic research that focuses on understanding and modifying pathways of functional decline.
PROJECT SUMMARY (See instructions): RCS The Metabolomics Core (RCS) has developed a diverse set of complementary metabolomics technologies that provide a rare combination of broad coverage and analytical precision, and deploys these tools in scientific and clinical collaborations that focus on metabolic signatures associated with functional decline in aging. The Duke Stedman Center's metabolomics core has been an integral component ofthe Duke's Pepper Older Americans Independence Center (OAIC) for the past 7 years and is now enhanced as an independent core. The metabolomics core is well known for its work in applying targeted mass-spectrometry (MS)-based metabolic profiling for understanding of disease and biological mechanisms. The Core will provide this analytic expertise to Pepper projects. Supported projects include: Pilot Projects (one in Year 1), Pepper Research Career Development awardees (two in Years 1-3), External Projects (five in Years 1-5), and future pilot and career development projects as they are selected and initiated. Ofthe external projects, one will characterize metabolomics biomarkers related to successful aging through the lifespan, and three interventional projects will critically address the modifiability of pertinent metabolites with treatments aimed at improving function (weight loss, protein supplements, exercise). Importantly, the lab has also developed and applied non-targeted gas chromatography (GC)/MS methods to obtain broader surveys of metabolic changes in biological systems. Use of non-targeted GC/MS allows measurement of analytes that are not included in the targeted modules, and thereby represents a tool for discovery and hypothesis formulation. Through activities of RC3, we propose to expand the scope ofthe targeted methods and have proposed two development projects that have evolved from our research in aging, thereby providing more powerful tools to support our work. It is also important to note that the RC3 team has recently engaged with other Pepper Centers, thereby forming important collaborative connections between the Duke Pepper OAIC and those groups. Success of RC3 will be highly innovative, because it will provide "one-stop shopping" access to comprehensive targeted (quantitative) and non-targeted (discovery) metabolomics tools via a single portal. Importantly, faculty and staff associated with this core are highly experienced in metabolic research, and will assist Duke's Pepper OAIC faculty and fellows with study design and interpretation, thus ensuring a maximally productive interaction of users with this core.
The Biochemical Pathways Core (RC2) provides a centralized resource for biomarker analyses in support of Duke Pepper OAIC projects in their work to understand and modify multiple pathways of functional decline. The Core provides the expertise to advise investigators on the biological and technical feasibility of assaying specific biomarkers and biomarker profiles for their utility as mediators and predictors of function and functional decline. For this funding cycle of the Duke OIAC, the RC2 Core will focus on assays of biochemical and inflammatory biomarkers related to the physical performance, metabolic health and longevity aspects of aging and functional status. The Core will provide this analytic expertise (performing ~2,000 assays annually) to Pepper projects. With the exciting new addition of Pathways Analysis (Ingenuity Systems) to our capabilities, we can aggregate our rapidly expanding biomarker data with published datasets of metabolomic, proteomic, and genomic findings to identify potential biological networks involved in the functional decline of aging. During the development phase of new studies, we will also serve as a resource for consultation about biomarkers and study designs to optimize grant preparation and the insights that might be achieved with biomarker analyses. The overall goals of this Core Facility will be to generate data on biomarkers of functional decline and their association with specific diseases; to incorporate Ingenuity Pathways Analysis to identify potential networks linking metabolomic, proteomic, and genomic markers; to develop new biomarkers of age-related oxidative stress; to determine if specific biomarkers and biological pathways identify individuals at risk for functional decline; and to monitor the efficacy of interventions designed to combat functional decline in aging. Supported projects include: Pilot Projects (one in Year 1), Pepper Research Career Development awardees (three in Years 1-3), External Projects (eight in Years 1-5), and future pilot and career development projects as they are selected and initiated. Of the external projects, three will characterize biomarkers related to successful aging through the lifespan, and five interventional projects will critically address the modifiability of pertinent biomarkers with treatments aimed at improving function. The application of biomarkers and pathways analysis to these intervention projects will provide objective insights into the efficacy and mechanisms of action of interventions .
