Subburaman Mohan, PhD
Research Professor
Departments of Biochemistry and Physiology
Assistant Chief
Musculoskeletal Disease Center
Jerry L. Pettis Memorial VA Medical Center
11201 Benton Street
Loma Linda, CA 92357
Phone: (909) 825-7084, extension 2932
Fax: (909) 796-1680
Email: Subburaman.Mohan@med.va.gov
Research Summary
The major focus of our work in the molecular genetics division of the musculoskeletal disease center is the application of several state-of-the art molecular genetics techniques to address fundamental questions in musculoskeletal biology, with particular emphasis on identifying novel genes and known genes as well as clarifying gene function for those genes involved in the musculoskeletal system. In our current work, we have placed a heavy emphasis on the mouse model to study genes related to: 1) peak bone density and bone size, two important determinants of bone strength; 2) regulation of soft tissue and hard tissue regeneration; 3) the mechanical performance of bone; and 4) the growth hormone/insulin-like growth factor axis.
To identify genes related to the musculoskeletal system, we employ a number of approaches. One of these approaches involves a quantitative trait loci (QTL) approach, which has been an important and powerful technique in modern mammalian genetics research. In the QTL approach, two inbred mouse strains exhibiting a phenotypic difference are crossed, and genetic loci that co-segregate with the phenotype are identified. Our mouse molecular genetics program also utilizes a phenotype-driven ethylnitrosourea chemical mutagenesis approach to identify genes relevant to the musculoskeletal system. In this approach, genetic changes (point mutations) are induced using chemicals in mice, which are then screened for various musculoskeletal phenotypes to identify mutant mice and genes that contribute to mutant phenotype. Other approaches we employ in our gene discovery program include whole genome microarray, yeast two hybrid screen, and informatics.
The approaches that we employ in our functional genomic studies for evaluation of gene function include both in vitro studies using various cell models and in vivo studies using various animal models. For studies to evaluate gene function, we utilize both transgenic overexpression and gene knock out approaches. Transgenes are overexpressed using either viral or cell type specific promoters. For knockout studies, we utilize siRNA as well as the cre/lox approach for cell type-specific disruption of gene of interest.
The clinical relevance of our current research in the molecular genetics program is as follows. The identification of genes that regulate bone density and bone size will help us to develop strategies to screen patients at risk for osteoporosis and to develop strategies to increase bone strength and thereby decrease incidence of osteoporosis. The successful identification of genes involved in soft and hard tissue regeneration would lead to strategies to treat injuries in military personnel and in the general population.Selected Publications
Miyakoshi N, Kasukawa Y, Richman C, Linkhart TA, Baylink DJ, Mohan S. Evidence that insulin-like growth factor binding protein-5 functions as a growth factor. J Clin Invest 107:73-81, 2001.
Amaar YG, Thompson GR, Linkhart TA, Chen ST, Baylink DJ, Mohan S. Insulin-like growth factor binding protein-5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). J Biological Chemistry 277:12053-12060, 2002.
Li XL, Mohan S, Gu W, Baylink DJ. Analysis of gene expression in the wound repair/regeneration process. Mammalian Genome 12:52-59,2001.
Mohan S, Richman C, Guo R, Amaar Y, Donahue LR, Wergedal J, Baylink DJ. IGF regulates peak bone mineral density in mice by both growth hormone-dependent and independent mechanisms. Endocrinology 144:929-936, 2003.
Kasukawa Y, Baylink DJ, Wergedal JE, Srivastava AK, Amaar Y, Guo R, Mohan S. Lack of IGF-I exaggerates the effects of calcium deficiency on bone accretion in mice. Endocrinology, 144 (11):4682-4689, 2003.
Srivastava AK, Mohan S, Wergedal JE, Baylink DJ. A genome-wide screen for N-ethylnitrosourea mutagenized mice for musculoskeletal phenotypes. Bone 33:179-191, 2003.
Xing W, Baylink D, Kesavan C and Mohan S. HSV-1 amplicon-mediated transfer of 128-kb BMP-2 genomic locus stimulates osteoblast differentiation in vitro. Biochem Biophys Res Comm 319: 781-786, 2004.
Srivastava AK, Masinde G, Yu H, Baylink DJ, Mohan S. Mapping quantitative trait loci that influence blood levels of alkaline phosphatase in MRL/MpJ and SJL/J mice. Bone.35(5):1086-94, 2004.
Eckstein F, Weusten A, Schmidt C, Wehr U, Wanke R, Rambeck W, Wolf E, and Mohan S. Longitudinal In Vivo Effects of Growth Hormone Overexpression on Bone in Transgenic Mice. J Bone Miner Res, 19 (5) 802-810, 2004.
Salih DA, Mohan S, Kasukawa Y, Tripathi G, Lovett FA, Anderson NF, Carter EJ, Wergedal JE, Baylink DJ, Pell JM. Insulin-like growth factor binding protein-5 (IGFBP-5) induces a gender-related decrease in bone mineral density (BMD) in transgenic mice. Endocrinology. In Press.