Sankar Lab

The research lab of Uma Sankar, PhD uses global and conditional knockout mouse models, biochemical, molecular biology and cell biology techniques as well as pharmacological inhibitors to investigate the mechanisms by which members of the Calcium/calmodulin dependent protein kinase (CaMK) signaling cascade, CaMKK2 along with its downstream kinases AMPK, CaMKI and CaMKIV; regulate the fate and function of bone marrow-derived mesenchymal stem cells, osteoblasts and osteoclasts.

Active Research

This lab team is pursuing in vivo translational studies investigating CaMKK2 inhibition as a bone anabolic strategy in accelerating fracture healing and combating age- and cancer-associated osteoporosis as well as osteoarthritis. Further, CaMKK2 is over-expressed in prostate cancer, and recent studies identify it to be a direct target of androgen receptor. Investigators here are interested in identifying the effects of CaMKK2 inhibition in prostate cancer-associated bone metastasis as well as establishing the identity of its downstream targets in prostate cancer as well as bone cells.

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Research Funding

The Sankar laboratory is funded by the American Cancer Society and the NIH.

2013, American Cancer Society Research Scholar –Sankar

2015, National Institutes of Health R01

Recent Publications: Role of CaMKK2 in Bone Cell Biology

Role of CaMKK2 in bone cell biology: Anabolic therapies in the treatment of osteoporosis are largely underdeveloped and form the highest clinical need. This lab team recently identified CaMKK2 as a novel regulator of osteoblast and osteoclast biology. Using a global knockout of this kinase as well as a selective pharmacological inhibitor, investigators identified a significant anabolic and anti-catabolic bone phenotype in mice when CaMKK2 expression is lost or its activity is inhibited. These studies are highly significant as anabolic therapies that can replace lost bone while inhibiting the catabolic arm of bone remodeling are of utmost clinical relevance. This is a recently developed project and two manuscripts are currently in review.

Sankar U, Pritchard ZJ, Voor MJ. Micro-computed tomography assisted distal femur metaphyseal blunt punch compression for determining trabecular bone strength in mice. J Biomech. 2016 May 3;49(7):1233-7 PMID: 26947030.

Pritchard ZJ, Cary RL, Yang C, Novack DN, Voor MJ, and Sankar U. Inhibition of CaMKK2 reverses age-associated decline in bone mass. 2015. Bone 2015 Jun;75:120-7. PMID: 25724145.

Cary R.L., W., S., Long, F., Novack, D.V., Racioppi, L., Voor, M. V. and Sankar U. 2013. Inhibition of CaMKK2 Stimulates Osteoblast Formation and Inhibits Osteoclast Differentiation. J Bone Miner Res, 2013; 28(7): 1599-610 PMID: 23408651.

Recent Publications: Osteoclast Biology

Osteoclast biology: My contributions to this field include the identification of the mechanism by which RANKL co-ordinates cell cycle exit during differentiation by osteoclast progenitors and the role of Microphthalmia transcription factor in osteoclast biology.

Sharma S. M., Ostrowski M. C and Sankar U. 2009. Defective Co-activator Recruitment in Osteoclasts from Microphthalmia-Oak Ridge Mutant Mice. Journal of Cellular Physiology: 220: 230-237; PMID: 19288495.

Hu R, Sharma S. M, Bronisz A, Sankar U and Ostrowski M. C. 2007. Eos, MITF and PU.1 Recruit Co-Repressors to Osteoclast Specific Genes in Committed Myeloid Precursors. Molecular and Cellular Biology. Jun;27(11):4018-2

Sankar U, Patel K, Rosol TJ and Ostrowski M. C. 2004. RANKL co-ordinates osteoclast differentiation with cell cycle exit through the up-regulation of CDK inhibitors, p27kip1 and p21cip1. Journal of Bone and Mineral Research. 19 (8): 1339-1348.

Meadows NA, Faulner G, Wells C, Ravasi T, Hume D, Sankar U, Hu R, Ostrowski M and Cassady A. 2004. Novel genes regulated by microphthalmia transcription factor in macrophages and osteoclasts. Journal of Bone and Mineral Research. 19 (Suppl. 1): S413-S413.

Mansky K. C, Sankar U, Han J and Ostrowski M. C. 2002. Microphthalmia Transcription Factor is a Target of the p38 MAPK Pathway in Response to Receptor Activator of NF-kB Ligand Signaling. The Journal of Biological Chemistry. 277(13): 11077-11083.

Bayoumi M, Sankar U and Muthusamy N. 2002. Role of macrophage stimulating factor and osteoclast differentiation factor in osteoclastogenesis of bone marrow derived stem cells. Indian Journal of Experimental Biology. 40: 995-1000.

Recent Publications: Role of CaMKIV and its Targets in Stem Cell Biology

Role of CaMKIV and its targets in stem cell biology: Using genetic knockout mouse models, we reported a role for CaMKIV in the control of hematopoietic stem cell (HSC) proliferation and survival. A subsequent microarray screen for downstream targets identified Growth Factor erv1-like (Gfer) to be significantly down-regulated in Camk4-/- HSCs. Using loss and gain-of-function experiments we found a key role for Gfer in HSC proliferation, similar to that of CaMKIV. Further investigations have revealed that Gfer regulates mitochondrial fission-fusion dynamics in embryonic stem cells. A manuscript showing the mechanism by which Gfer regulates the mitochondrial fission GTPase Drp1 is under review.

Teng, E.C., Todd, L.R., Ribar, T.J., Lento, W., Dimascio,L., Means, A.R. and Sankar, U. 2011. Gfer Inhibits Jab1-Mediated Degradation of p27kip1 to Restrict Proliferation of Hematopoietic Stem Cells. Molecular Biology of the Cell: 22, 1312-1320; PMID: 21346186.

Sankar, U., and Means, A.R. (2011). Gfer is a critical regulator of HSC proliferation. Cell Cycle 10(14), June 4, 2011, PMID: 21636978.

Wilkerson D.C., and Sankar, U. 2011. Mitochondria: A sulfhydryl oxidase and fission GTPase connect mitochondrial dynamics with pluripotency in embryonic stem cells. Int J Biochem Cell Biol Sep;43(9):1252-6; Epub 2011 May 13, PMID: 21605695

Todd, L.R., Damin, M.N., Gomathinayagam, R., Horn, S.R., Means, A.R., and Sankar, U. 2010. Growth Factor erv1-like Modulates Drp1 to Preserve Mitochondrial Dynamics and Function in Mouse Embryonic Stem Cells. Molecular Biology of the Cell: Vol. 21, 1225–1236, April 1, 2010; PMID: 20147447.

Todd, L.R., Gomathinayagam, R. and Sankar U. 2010. A novel Gfer-Drp1 link in preserving mitochondrial dynamics and function in pluripotent stem cells. Autophagy: Aug 16; 6(6):821-822; PMID: 20581476.

DiMascio L, Voermans C, Uqoezwa M, Duncan A, Lu D, Wu J, Sankar U, and Reya T 2007. Identification of Adiponectin as a Novel Hemopoietic Stem Cell Growth Factor. Journal of Immunology. 178: 3511 – 3520.

Kitsos C*, Sankar U*, Ilario M, Colomer J, Duncan A. W, Reya T and Means, A. R. 2005. Calmodulin-Dependent Protein Kinase IV Regulates Hematopoietic Stem Cell Maintenance. The Journal of Biological Chemistry. 280(39): 33101-33108; PMID: 16020540. (*Sankar and Kitsos contributed equally). JBC paper of the week.

Recent Publications: Role of CaMKs in Other Cells and Cancer

Role of CaMKs in other cells and Cancer: The Sankar Lab team identified the mechanism by which CaMKIV links Toll-like receptor 4 signaling with the survival pathway in dendritic cells. Another collaborator manuscript showing the role of CaMKK1 in thymocyte aging is under review. More recently, this investigator team identified a novel cross-talk between CaMKIV and CaMKII in the regulation of proliferation of myeloid leukemia cells.

Monaco S., Rusciano MR, Maione AS., Soprano M., Gomathinayagam R., Todd LR., Campiglia P., Salzano S., Pastore L., Leggiero E., Wilkerson DC., Rocco M., Selleri C., Iaccarino G., Sankar U* and Illario M*. A novel cross-talk between calcium/calmodulin kinases II and IV regulates leukemia cell proliferation. Cell Signal. 2015 Feb;27(2):204-14. doi: 10.1016/j.cellsig.2014.11.007. Epub 2014 Nov 15. PMID: 25446257.

Illario M., Di Somma C., Iaccarino G., Campiqila P, Sankar U and Montnuri N. (2014) Novel therapeutic targets in metabolic disorders: from bench to bedside. Scientific World Journal 2014; 2014:365974. doi: 10.1155/2014/365974. Epub 2014 May 13. PMID: 24959610.

Harrison BJ, Flight RM, Gomes C, Venkat G, Ellis, SR, Sankar U., Twiss JL, Rouchka, EC, and Petruska JC. (2014) IB4-binding sensory neurons in the adult rat express a novel 3’ UTR-extended isoform of CaMK4 that is associated with its localization to axons. J Comp Neurol 2014 Feb 1; 522(2):308-36 PMID: 23817991.

Guideline Review (Invited Participation)

Klionsky DJ, Abdalla FC, Abeliovich H, …., Sankar U, et al. 2012. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012 April; 8(4): 445-544; PMID: 22966490.

Illario M, Giardino-Torchia LM, Sankar U, Ribar TJ, Galgani M, Vitiello L, Masci AM, Bertani F, Ciaglia E, Astone D, Malucci G, Cavallo A, Viatle M, Cimini V, Pastore L, Means A. R., Rossi G, Racioppi L. 2008. Calmodulin-Dependent Kinase IV links Toll like receptor 4 signaling with Survival Pathway of Activated Dendritic Cell Survival. Blood, Jan 15 2008;111(2):723-31; PMID: 17909078.

Faculty Research Team

Uma Sankar, PhD

Associate Professor of Anatomy, Cell Biology & Physiology

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Additional Research Team Members

Other research team members in the Sankar Lab include Ushashi Dadwal (postdoc), Elsa Mevel (postdoc), Mavis Irwin (postdoc), Justin Williams (IBMG PhD Student), Anuradha Valiya Kambrath (research analyst), Roshni Bharati Patel (MD student), Eric Chang (undergraduate student), and Matthew Hartman (undergraduate student).