Chandrasekhar Kesavan Ph. D

Exercise is an important stimulator and regulator of bone growth and maintenance and thus has been used as a strategy to improve bone quality in humans to prevent loss of bone mass and diseases like osteoporosis and to lower fracture risk. However, there are conditions such as injury, disease, trauma and aging where exercise is not feasible. In order to improve bone mass in these patients, my research has focused on identifying genes that respond to exercise and to increase understanding of the mechanism of how exercise benefits bone using animal model. Determining mechanisms can lead to the identification of potential novel therapeutic strategies and therapeutics which activate these mechanisms using small molecule therapeutics in patients where exercise is not an option. Towards this goal, I have performed mouse genomic mapping by comparing two inbred mouse strains that respond differently to exercise and I have identified novel genetic loci/candidate genes that contribute to the skeletal anabolic response to exercise. I have demonstrated that osteoblast derived IGF-I is an important mediator of the skeletal anabolic response to exercise in an IGF-I knockout mouse model, and that IGF-I – estrogen cross-talk is essential for the bone response. In terms of potential novel downstream targets of IGF-I, I have recently found, that IGF-I is a critical regulator of microRNA20a expression in bone cells. I have also recently reported that mice with disruption of the miR17-92 cluster in osteoblast lineage cells impairs periosteal bone formation, a phenotype also observed in osteoblast specific IGF-I conditional knockout mice. Presently, I have provided novel evidence that TCF7L2 is one of many upstream regulators of the IGF-I gene and that TCF7L2, a gene associated with type-2 diabetes, is essential for skeletal homeostasis. I have performed in vitro assays using specific inhibitors and have identified a new pathway which regulates TCF7L2 expression during bone formation. I am currently screening additional downstream targets to evaluate their functional relevance in regulating bone forming osteoblast function.

The second area of my research is focused on identification of therapeutic molecules which target key biological bone forming pathways for delivery in a scaffold. Towards this goal, my research has used a computational approach in collaboration with Alagappa University, India. We have identified and tested the therapeutic potential of several small molecule agonists which affect the, BMPR1A, FGFR, Vitamin D receptors involved in mediating bone anabolic signals using in vitro models.  I am also evaluating whether the FDA approved small molecules that target other receptor for the treatment of diseases other than bone have s potential in stimulating bone forming osteoblast function. Currently, I am developing novel osteoinductive scaffolds, designing and printing bone like scaffolds using 3D approach for delivering small molecules that promote healing of bone fractures or segmental defects. 

In addition to basic research, I am also involved in clinical research in the Gastroenterology Department at the VA Loma Linda. Veterans with GI problems, especially those who have inflammatory bowel disease (IBS), IBS-diarrhea (D), Crohn’s disease and angiodysplasia experience a poor quality of life, loss of independence, increased mental stress. There need for extensive medical treatment contribute to excessively high VA healthcare costs. In order to improve the quality of life in these Veterans and to reduce rising VA healthcare costs, my research has focused on identifying key cost determinants by performing retrospective studies in collaboration with Dr. Richard Strong.   These studies include: 1) How Vitamin D deficiency contributes to IBS-D and that supplementation of Vitamin D (3000 units) daily reduces symptoms; 2) How Iron replacement therapy was effective while growth hormone therapy which is very expensive with minimal effect for Angiodysplasia which led to the development of an algorithm  for treatment of GIADs and 3) Showing that Endocuff -assisted endoscopy to detect GI- bleeding was very effective vs endoscopy alone to detect and treat patient’s symptoms and reduce emergency admissions. Overall, our clinical research is focused on the development of precision medicine strategies for GI clinicians to improve the Veterans quality of life.

Recent publication 

1. Weirong X, Kesavan C, Pourteymoor S, Mohan S. Global and Conditional Disruption of the Igf-I Gene in Osteoblasts and/or Chondrocytes Un-veils Epiphyseal and Metaphyseal Bone-Specific Effects of IGF-I in Bone. Biology, Sep 12;12(9); 1228. MDPI Journals, 2023.
2. Kesavan C, Das A, Goyal P, Jackson CS, Strong DD, Strong RM. Vitamin D deficiency (VDD) in Veterans with IBS-D and Benefits of supplementation, Diagnostics (Basel), 13(17):2807, 2023, PMID: 37685345
3. Gutierrez M, Kesavan C, Das A, Jackson CS, Strong RM. Strategic Management of Bleeding Small Bowel Gastrointestinal Angiodysplasias (GIADs): A 12-year Retrospective Review in a Veteran Population and Cost Comparison, Diagnostics (Basel), 13(3): 525, 2023. PMID: 36766630.
4. Mohan S, Pourteymoor S, Kesavan C. WNT16 Regulation of the Articular Chondrocyte Phenotype in Mice. Life (Basel). 2023 Mar 25;13(4):878. doi: 10.3390/life13040878.PMID: 37109407 
5. Kesavan C, Gustavo AG, Pourteymoor S, Mohan S, Development of an animal model for traumatic brain injury augmentation of heterotrophic ossification in response to local injury, Biomedicines, 2023 Mar 18;11(3):943. doi: 10.3390/biomedicines11030943.PMID: 36979922.