LaDora V. Thompson - US grants

DESCRIPTION: (Verbatim from application) Our long-term goal is to determine the molecular mechanisms underlying the diminished performance of muscle with are. Our overall hypothesis is that the age-related decline in muscle performance is due to cellular and molecular changes in key muscle proteins. The focus of this proposal is myosin, the major contractile protein in muscle. Our hypothesis is that the decline in force-generating capacity with age is due to specific structural alterations in myosin, resulting from accumulation of post-translational modifications. We will test this hypothesis by performing physiological, biophysical and biochemical investigations of myosin from rats of different ages. The following aims will be pursued using hindlimb muscles of rats aged 10, 22. 24. 26. and 28 months. AIM 1. Determine age-related differences in single fiber force-generating capabilities. The force-generating capacity of single fibers will be determined using a permeabilized fiber preparation. A sensitive microgel technique will be used to identify myosin heavy chain isoform content of the fibers to determine muscle fiber type. We hypothesize that there will be a decline in the force-generating capacity of individual type I and type II fibers with age. AIM 2. Use site-directed EPR spectroscopy to determine age-related changes in myosin structure. Spin labels will be attached to a selected site on the myosin head within muscle fibers and then EPR will be used to detect age-related changes in myosin structure during contraction. The advantage of EPR is its high resolution, which can detect and quantitate the distribution of structural states corresponding to the weak-and strong-binding intermediates of myosin. We hypothesize that the age-related decline in force generation is a result of a decrease in the strong-binding structural state of myosin. AIM 3. Determine age-related post-translational chemical modifications in myosin. Levels of nitrotyrosine, sulfhydryls, and carbonyls in myosin will be determined. We hypothesize that there are increases in post-translational chemical modifications in myosin causing alterations in myosin protein structure resulting in decreased force production. The results will be invaluable for understanding the molecular mechanisms of cellular aging.

[unreadable] DESCRIPTION (provided by applicant): Funds are requested to provide partial support for the Gordon Research Conference (GRC) on the Biology of Aging. The theme of the 2007 conference will be "Maintenance of Macromolecular Integrity in Aging" to be held at the Les Diablerets Conference Center, Les Diablerets, Switzerland, from September 23 - 28, 2007. Drs. LaDora V. Thompson, Holly Brown-Borg and Alexander B[unreadable]rkle will organize the scientific program. Our aim here is to provide funds to support invited speakers, discussion leaders, and junior scientists (postdoctoral fellows, advanced graduate students, or new, junior faculty) who would benefit from and contribute to the conference. The speakers we have invited are internationally recognized for their research on the molecular and cellular biology of aging, physiology of aging, and genetics of aging. These speakers are known to be strong communicators of their science, who stimulate, and participate in, lively discussion. Accumulating damage of DNA has long been suggested as one of the major forms of damage that contribute to the aging process, and life spans of mammalian species positively correlate with the cellular capacity for DNA repair. But other biological macromolecules such as proteins and lipids are also known to undergo molecular damage, aggregation, and misfolding which could contribute to the aging process. Stem cells and nuclear receptors are currently being intensively investigated in their contribution to the aging process. In recent years, a large number of genetic, pharmacological and dietary interventions have been described that slow down aging in various systems ranging from unicellular organisms to humans. Many such interventions have been mechanistically linked with cellular maintenance functions and/or cellular stress resistance; they can be expected to reduce the vulnerability of cells and tissues and thus prevent age-related pathological changes. Lastly, models of accelerated aging have enhanced our understanding of cellular maintenance and stress resistance. The Gordon Research Conference will focus on these hot topics. The rationale behind the choice of these themes is the remarkable convergence of the results from the models systems to investigate cellular maintenance and integrity. The goals of the conference:-To critically assess progress in the biology of aging; To determine whether the biology of aging informs on the nature/causes of age-related decline and disease; To emphasize integrative and translational research findings as a means to develop novel future avenues for therapeutic options that extend health span. The overall purpose of the Gordon Research Conference on The Biology of Aging, "Maintenance of Macromolecular Integrity in Aging" is to bring together investigators in diverse areas of aging and investigators outside the field to discuss the current research in the field and to consider the potential to translate scientific progress into clinical interventions. The ability of cellular macromolecules (e.g., DNA, proteins, lipids) to maintain integrity, using various cellular processes (e.g. repair, degradation and replacement) and several model systems (C. elegans, rodents, fungal, accelerated aging models), is at the forefront of the biology of aging and the extension of health span. We fully anticipate that progress in this field will pave the way for interventions and quality of life for the older adult. [unreadable] [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): We seek support for an interdisciplinary Training Program in Functional Proteomics of Aging for both predoctoral and postdoctoral trainees at the University of Minnesota. This Training Program contains two major components: (1) Research training that focuses on the use of proteomic technology to reveal the molecular details behind the age-related loss in tissue function. (2) Didactic and experiential training in gerontology and proteomics to provide trainees with a solid foundation for launching successful careers in aging research. The research component of this Training Program consists of three research areas that focus on retaining physiological function during aging: muscle (Thomas, Thompson, Lowe, Arriaga, Ervasti), the central nervous system (Olsen, Ferrington, Low, Ervasti) and metabolism and longevity (Bernlohr, Arriaga, Griffin, Hendrickson, Kim, Low). These Program Faculty members are drawn from two graduate programs at the University of Minnesota: Biochemistry, Molecular Biology and Biophysics (BMBB) and Rehabilitation Sciences (RSc). Proteomic analysis is utilized by Training Faculty to reveal altered protein content, binding partners, and post-translational modifications that occur in aged tissue. This information aids in determining the mechanistic basis for age-related changes in protein structure and function. Our research is supported by outstanding cores equipped with a variety of state-of-the-art mass spectrometers, such as the Center for Mass Spectrometry and Proteomics, and other analytical equipment in Training Faculty laboratories. The Training Program will also include both didactic training via coursework in gerontology and proteomics, as well as experiential training in aging research via seminars, symposia, journal clubs, and group meetings with Program Faculty members. Completion of the Training Program coursework will qualify trainees for a Gerontology Graduate Minor, thus providing direction for trainees' future career goals. The experiential training is designed to maximize interaction among trainees and Training Faculty from multiple labs. In summary, the primary goal of this Training Program is to help exceptional young scientists develop the intellectual and technical tools needed for productive careers as independent investigators and educators in aging research. [unreadable] [unreadable] [unreadable]

SUMMARY This proposal requests funds to support the 2017 Gordon Research Conference (GRC) and Gordon Research Seminar (GRS) on Oxidative Stress & Disease. The GRC will be held at the Renaissance Tuscany, in Il Ciocco, Barga, Italy, on March 19-24, 2017. The GRS, which is a meeting organized by young investigators in the field, will be held at the same site prior to the GRC on March 18-19. This will be the 9th GRC conference on Oxidative Stress & Disease and the 4th GRS associated with this specific GRC. The title of the 2017 GRC is ?Redox Biology in Disease and Translational Medicine? and is focused on questions and approaches at the forefront of the field of redox biology, with particular emphasis on cutting edge basic research with high translational potential to eliminate disease, improve quality of life and promote healthy longevity. The program will encompass a range of topics, including recent insights into ROS/RNS signaling and its translational potential; advances in our understanding of proteostasis and mitochondrial quality in longevity; the role of ROS/RNS in human health, inflammation and disease progression; and initial strategies currently being applied for translation of basic redox biology research discoveries into the clinical realm. The emphasis will be on the explosive new developments in the field in terms of central principles of redox biology. The GRC program draws from a diverse field of scientists and clinicians and therefore should be very multidisciplinary in nature and foster new collaborations. The program includes a balanced slate of internationally recognized Speakers and Discussion Leaders: 39% are women, 17 international speakers (55%) are from four continents, and 32% of the program participants are mid- or early-career investigators. The requested funds will support overall conference goals, which include: (1) delivery of cutting-edge science by ?emerging? and senior leaders in the field, (2) promote the interaction of meeting participants from diverse backgrounds (i.e., career stage, country of origin, research specialty and focus), and (3) enhance the careers of young investigators by attending an international meeting of superior caliber. These goals will be met through the following aims: Aim 1: Bring together an audience of basic and clinical scientists who approach the field of redox biology and disease from diverse perspectives to share their latest findings and methodologies. Emphasis is placed on research that provides new insight into the mechanisms of disease and has high potential for the development of translational therapeutics to promote healthy living. Aim 2: Promote interactions and the free exchange of ideas among scientists, clinicians and trainees of different disciplines and at different stages of their career to stimulate further research on redox biology. Aim 3: Allow networking with premiere scientists with diverse backgrounds, in order to forge new understanding and develop new collaborations. Aim 4: Evaluate meeting effectiveness in achieving its goals to present the latest research, create a forum for debate, and encourage participation of trainees and junior scientists in order to improve future meetings.