R01AR077042

Preserving Physical Function in Patients with Kidney Disease - Project Summary/Abstract

Skeletal muscle dysfunction contributes to frailty, disability, and mortality in patients with chronic kidney disease (CKD). This proposal seeks to determine if muscle dysfunction in CKD can be alleviated by dialysis (blood filtration for kidney failure). We recently discovered that patients with CKD experience progressively worsening muscle fibrosis, and that greater severity of fibrosis is associated with reduced muscle strength and physical function.

In patients with severe CKD, fibrotic changes are extensive. However, despite the seemingly advanced nature of this fibrotic transformation, patients starting dialysis experienced marked improvement in fibrosis. This suggests that, in patients with severe CKD and muscle fibrosis, the initiation of dialysis could improve physical function. Therefore, this proposal tests the highly innovative hypothesis that the initiation of dialysis in patients with severe CKD reverses muscle fibrosis and improves physical function.

We will accomplish this objective using a translational approach that integrates clinically relevant functional endpoints with state-of-the-art methods including muscle tissue mechanics, quantitative magnetic resonance imaging (QMR), and transcriptomic and proteomic studies of human skeletal muscle.

The proposed human studies will:

1. Define the effect of dialysis initiation on muscle fibrosis by examining changes in muscle collagen content, collagen cross-linking, tissue passive stiffness, and QMR measures.
2. Determine the extent to which regression of fibrosis after dialysis initiation translates into functional improvements by testing the association of alterations in the structural parameters from Aim 1 with changes in muscle strength, endurance, and lower extremity performance.
3. Identify molecular and cellular predictors of the resolution of fibrosis using transcriptomic and proteomic analyses of skeletal muscle.

If our hypotheses are correct:
1. Muscle fibrosis could be an indicator for physicians to start dialysis therapy.
2. This proposal will identify an intervention to alleviate muscle dysfunction in patients with CKD.

Albert Einstein College Of Medicine

THE NATIONAL INSTITUTE OF AND MUSCULOSKELETAL AND SKIN DISEASES (NIAMS) MISSION IS TO SUPPORT RESEARCH INTO THE CAUSES, TREATMENT, AND PREVENTION OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES, TRAINING OF BASIC AND CLINICAL SCIENTISTS TO CARRY OUT THIS RESEARCH, AND DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN THESE DISEASES. THE EXTRAMURAL PROGRAM PROMOTES AND SUPPORTS BASIC, TRANSLATIONAL, AND CLINICAL STUDIES OF SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES, SKIN BIOLOGY AND DISEASES, BONE BIOLOGY AND DISEASES, MUSCLE BIOLOGY AND DISEASES, AND JOINT BIOLOGY AND DISEASES AND ORTHOPAEDICS. NIAMS SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES PROGRAMS ADDRESS BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS AND OBSERVATIONAL AND MECHANISTIC STUDIES, FOCUSED ON IMMUNE-MEDIATED ARTHRITIS AND AUTOIMMUNE-RELATED ACUTE AND CHRONIC DISORDERS IN ADULTS AND CHILDREN. NIAMS SKIN BIOLOGY AND DISEASES PROGRAMS SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN SKIN, INCLUDING BOTH COMMON AND RARE SKIN DISEASES. THESE PROGRAMS INCLUDE INVESTIGATIONS OF THE BASIC MOLECULAR, CELLULAR, AND DEVELOPMENTAL BIOLOGY OF SKIN, AS WELL AS STUDIES OF SKIN AS AN IMMUNE, SENSORY, ENDOCRINE, AND METABOLIC ORGAN. NIAMS BONE BIOLOGY AND DISEASES PROGRAMS SUPPORT RESEARCH ON THE CONTROL OF BONE FORMATION, RESORPTION, AND MINERALIZATION AS WELL AS THE EFFECTS OF SIGNALING MOLECULES ON BONE CELLS. THEY SUPPORT CLINICAL STUDIES OF INTERVENTIONS TO PREVENT FRACTURES ASSOCIATED WITH OSTEOPOROSIS AND RESEARCH INTO LESS COMMON BONE DISEASES. NIAMS MUSCLE BIOLOGY AND DISEASES PROGRAMS ENCOURAGE RESEARCH ON MUSCLE DEVELOPMENTAL BIOLOGY, GROWTH, MAINTENANCE, AND HYPERTROPHY, PHYSIOLOGY OF CONTRACTION, STRUCTURAL BIOLOGY OF THE CONTRACTILE APPARATUS, DISEASE MECHANISMS, BIOMARKERS AND OUTCOME MEASURES, AND DEVELOPMENT AND CLINICAL TESTING OF THERAPIES FOR CONDITIONS INCLUDING THE MUSCULAR DYSTROPHIES. NIAMS JOINT BIOLOGY, DISEASES, AND ORTHOPAEDICS PROGRAMS SUPPORT A BROAD SPECTRUM OF RESEARCH CENTERED ON THE INTERPLAY AMONG THE BODY'S MUSCLES, BONES, AND CONNECTIVE TISSUES. THEY ENCOURAGE TISSUE ENGINEERING AND REGENERATIVE MEDICINE RESEARCH, MOLECULAR BIOLOGY, IMAGING, AND CLINICAL RESEARCH, AND THE TREATMENT AND PREVENTION OF ORTHOPAEDIC CONDITIONS. NIAMS PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.846 - Arthritis, Musculoskeletal and Skin Diseases Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

Bronx, New York 10461 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 340% from $778,679 to $3,428,324.