While the importance of osteoporosis as a major, and growing, public health problem is now well recognized, there remain significant gaps in our clinical and basic understanding of this disorder. Thus, the overall goal of this Program Project Grant (PPG) is to better define the pathogenesis and population impact of age-related bone loss and fractures. As in the past, the major strength of our group is to bring together diverse disciplines into synergistic interactions, and the present application includes clinical-investigatve studies in the Clinical Research Unit (CRU) in Project 1, population-based epidemiology studies in Project 2, and basic mouse/cellular studies in Project 3. The three Projects are supported by an Administrative and Biostatistics Core. Although the approaches being used in each of the Projects differ, the central theme of this PPG, which is addressed by Aim 1 of each Project, is to better understand the role of the sympathetic nervous system (SNS) in regulating bone metabolism and age-related bone loss. Thus, the effects of increased sympathetic outflow in contributing to impaired bone formation and increased bone resorption with aging in estrogen (E)- deficient postmenopausal women are addressed by Aim 1 of Project 1, whereas the population impact of an important age-related clinical condition associated with increased sympathetic outflow, heart failure (HF), will be studied in Aim 1 of Project 2. Similarly, Aim 1 of Project 3 will use mouse models to examine potential interactions between SNS and E signaling in bone. Subsequent Aims of each Project remain closely related to the first Aim, but address more Project-specific issues relevant to age-related bone loss and fractures. Thus, Project 1 will also identify other, fundamental mechanisms responsible for the age-related impairment in bone formation. For the latter studies, we will utilize novel techniques developed in our laboratory to isolate highly enriched populations of osteoblasts and osteocytes from human needle bone biopsies and analyzed without the need for in vitro culture. Project 2 will enhance fracture risk assessment and identify clinically relevant pathophysiologic mechanisms from a population-based perspective. Thus, in addition to evaluating the impact of HF on fracture risk, these studies will address the major unresolved issue of how emerging comorbid conditions interact to determine fracture risk with aging. Project 3 will employ mouse models to examine potential interactions between SNS and E signaling in bone. These studies will also fill important gaps in knowledge regarding E regulation of bone turnover by using conditional deletion of estrogen receptors [ERs] and in adult mice, thereby differentiating the role of these receptors in skeleta development versus in regulation of the adult skeleton. The Core will provide administrative leadership, critical infrastructure, and the biostatistical and bioinformatics resources needed for the three Projects.

Public Health Relevance

Osteoporosis is an enormous public health problem. Each year, there are approximately 2 million osteoporosis-related fractures, with a net cost to the US health care system of $17 billion. The key to prevention, as well as developing more physiologically relevant treatments, is a better understanding of the pathogenesis and population impact of this disorder, which is the goal of our Program Project Grant.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG004875-35
Application #
9692593
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Joseph, Lyndon
Project Start
1997-07-01
Project End
2021-04-30
Budget Start
2019-05-15
Budget End
2021-04-30
Support Year
35
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Bower, James H; Grossardt, Brandon R; Rocca, Walter A et al. (2018) Prevalence of and indications for antipsychotic use in Parkinson's disease. Mov Disord 33:325-328
Rocca, Walter A; Grossardt, Brandon R; Brue, Scott M et al. (2018) Data Resource Profile: Expansion of the Rochester Epidemiology Project medical records-linkage system (E-REP). Int J Epidemiol 47:368-368j
Xu, Ming; Pirtskhalava, Tamar; Farr, Joshua N et al. (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246-1256
Khosla, Sundeep; Farr, Joshua N; Kirkland, James L (2018) Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis. J Clin Endocrinol Metab 103:1282-1290
Rocca, Walter A (2018) The future burden of Parkinson's disease. Mov Disord 33:8-9
Rocca, Walter A; Gazzuola Rocca, Liliana; Smith, Carin Y et al. (2018) Personal, reproductive, and familial characteristics associated with bilateral oophorectomy in premenopausal women: A population-based case-control study. Maturitas 117:64-77
Drake, Matthew T; Fenske, Jennifer S; Blocki, Frank A et al. (2018) Validation of a novel, rapid, high precision sclerostin assay not confounded by sclerostin fragments. Bone 111:36-43
Laughlin-Tommaso, Shannon K; Khan, Zaraq; Weaver, Amy L et al. (2018) Cardiovascular and metabolic morbidity after hysterectomy with ovarian conservation: a cohort study. Menopause 25:483-492
Farr, Joshua N; Weivoda, Megan M; Nicks, Kristy M et al. (2018) Osteoprotection Through the Deletion of the Transcription Factor Ror? in Mice. J Bone Miner Res 33:720-731
Wenning, Gregor; Trojanowski, John Q; Kaufmann, Horacio et al. (2018) Is multiple system atrophy an infectious disease? Ann Neurol 83:10-12

Showing the most recent 10 out of 401 publications