James G Tidball

Professor, Integrative Biology And Physiology, University of California Los Angeles

Professor, Pathology and Laboratory Medicine, University of California Los Angeles

(310) 206-3395

Terasaki Life Science Building
Molecular, Cellular & Integrative Physiology Program
UCLA
Los Angeles, CA 90095 Dept of Pathology and Laboratory Medicine
UCLA
Los Angeles, CA 90095

Office Phone Number:
(310) 206-3395

UC Profile
http://www.physci.ucla.edu/DMD/index.php

Research in the Tidball lab is directed toward understanding processes that regulate skeletal muscle wasting and regeneration. Exploring the mechanisms through which the immune system can modulate skeletal muscle wasting, injury, regeneration and growth is a particular focus of the lab. Discoveries in the our lab over the past 25 years have shown that immune cells, especially myeloid cells, play a major role in modulating muscle injury and repair that occur in chronic, muscle wasting diseases and following acute injuries. For example, our findings have shown that macrophages and eosinophils are key effector cells in the pathogenesis of Duchenne muscular dystrophy. Ongoing investigations in the lab are revealing the identity of specific molecules released by myeloid cells that promote muscular dystrophy. However, discoveries in our lab have also shown that regulatory interactions between cytotoxic, M1 macrophages in dystrophic muscle and anti-inflammatory, M2 macrophages are important in regulating the balance between the death of dystrophic muscle and regenerative processes. This work showed that the experimental manipulation of the balance between the functions of M1 and M2 macrophages can affect the severity of muscular dystrophy, suggesting that manipulation of macrophage phenotype in vivo may have potential therapeutic value for the treatment of the disease. We are now building on those findings in an NIH-funded preclinical investigation in which we are testing whether pharmacological manipulations of co-stimulatory signals that macrophages provide to T-lymphocytes can attenuate the pathology of muscular dystrophy. Other NIH-funded investigations in our lab explore epigenetic mechanisms through which an anti-aging protein called Klotho affects myogenesis and muscle regeneration in neonatal and aging muscle. We are also determining how those Klotho-driven epigenetic regulatory influences affect muscle growth following acute muscle injury or exercise.

Affiliations

Member, Brain Research Institute

Research Interests

Much of the research in my lab concerns the cell biology of muscle disease. We are particularly interested in the pathophysiology of muscular dystrophy that is caused by null mutations of the gene that encodes the membrane associated protein called dystrophin. Loss of dystrophin from humans causes the lethal, progressive disease called Duchenne muscular dystrophy (DMD). Although loss of dystrophin is the primary cause of DMD, the resulting muscle pathology is difficult to interpret in the simple context of loss of a single structural protein. Instead, current evidence tells us that the secondary loss of other, dystrophin-associated proteins is important in causing many of the pathological features of the disease. One of these dystrophin-associated proteins, called nitric oxide synthase (NOS), produces the important regulatory molecule NO, and its loss can result in misregulation of many vital processes and thereby contribute to the pathology of muscular dystrophy. Much of our current work is directed toward understanding the functions of NO in muscle and the relationships between NO defects and muscular dystrophy. We have also learned through our recent studies that the immune system contributes importantly to promoting the pathology of muscular dystrophy. We have found that both lymphoid and myeloid cells increase the death of dystrophic muscle, which suggests that immune-based therapeutics may provide a new approach to treating muscular dystrophy. Our continuing work on this project is directed toward elucidating the mechanisms through which the immune system, especially myeloid cells, causes death of dystrophic muscle. In addition, we are exploring the possibility that other subpopulations of myeloid cells may also promote regeneration of injured tissue, and provide insights into new therapeutic strategies.

Biography

Interactions between skeletal muscle and the immune system. A major project in our lab concerns the pathophysiology of muscular dystrophy (dystrophinopathy). Our research has shown that the immune system plays an important role in influencing the severity of muscular dystrophy, and that immune-based interventions can significantly reduce dystrophic muscle pathology and promote muscle regeneration. Our continuing efforts are directed toward identifying the key effector cells and molecules involved in influencing the course of the disease, and examining the interplay between those effectors. Our technical approaches include the generation and analysis of transgenic, dystrophic mice so that the effects of increased or decreased expression of selected effector molecules can be assessed. We also examine the systemic effects of experimental depletions of selected immune cell populations and the efficacy of selected, pharmaceutical interventions on the progress of the disease. In other studies, we are studying the mechanisms through which the immune system influences the wasting of skeletal muscle that occurs during aging, a process called sarcopenia. We are particularly interested in identifying the mechanisms through which specific populations of myeloid cells affect muscle wasting and regeneration, and identifying strategies to slow the wasting process.

Publications