Department of Physiology & Pennsylvania Muscle Institute, University of Pennsylvania
A601 Richards Building
3700 Hamilton Walk
Philadelphia, PA 19104
Phone: (215) 573-2640
Duchenne's Muscular dystrophy, Synapse-specific gene regulation, Extraocular muscle, utrophin, myostatin, gene therapy
Cloning genes, GeneChip screening, promoter analysis, expression of recombinant proteins, generation of antibodies, imaging, physiological evaluation of muscle, laser capture microscopy
National Talent Search (NTS) Scholarship, National Council for Education, Research & Training, India (1979-85); Neuromuscular Disease Fellowship, Muscular Dystrophy Association, USA (1994-95); Clinical Investigator Development Award (CIDA), National Institutes of Health, USA (1995-98); Presidential Early Career Awards for Scientists and Engineers (PECASE), Executive Office of the President, USA (2005)
We study molecular mechanisms underlying muscle specializations and patho-physiology of muscle diseases. Topics include developmental changes of muscle as a whole that lead to the formation of unique skeletal muscle group such as the extraocular muscle (EOM), control of muscle size by growth/developmental factors, as well as formation of neuromuscular junctions (NMJ). This research is also interesting from a disease perspective since some of these molecules/pathways (e.g. myostatin, utrophin) offer therapeutic strategies for muscular dystrophy.
are anatomically and physiologically distinct from other mammalian striated muscles. From a disease perspective, EOM have a predilection for involvement in myasthenia gravis, while enigmatically they are spared in muscular dystrophy. It is currently unclear why EOM are selectively involved or spared in different diseases but it is generally accepted that group-specific properties play an important role in terms of their patho-physiology. We use a variety of techniques including GeneChips/DNA microarrays to identify and clone genes selectively expressed in EOM. Detailed characterization of genes expressed in the EOM should allow us to define the molecular makeup of this muscle group and help understand their unique patho-physiology.
is considered to be the autosomal homolog of the Duchenne's muscular dystrophy locus. Utrophin is selectively concentrated at locales such as the Blood-Brain Barrier (BBB) in brain and the NMJ and myotendinous junctions in muscle. Selective concentration at the NMJ, occurs in part by synapse-specific transcriptional (promoter) activation of the utrophin by neurite associated growth/differentiation factors (e.g. heregulin). We use techniques such as promoter mutagenesis, DNA affinity chromatography and cDNA cloning to identify transcriptional regulators of the utrophin gene and characterize their signaling pathways to determine the overall mechanism of regulation of utrophin in muscle. Since utrophin overexpression can reverse muscular dystrophy in mice, we have been delivering the genes/molecules that we identify as being able to upregulate utrophin to dystrophic muscle, in an attempt to treat muscular dystrophy. We use a number of anatomical, biochemical and physiological parameters to address whether the gene therapy/promoter activation trial has been therapeutic in the mdx mouse model of muscular dystrophy.
is a novel negative regulator of muscle mass. The myostatin gene when mutated causes the increased musculature seen in Belgian blue cattle and mice. Inhibition or blockade of endogenous myostatin offers a potential means to compensate for the severe muscle wasting that is pathognomic of muscular dystrophy. We are interested in developing and testing blockade of myostatin protein in vivo, as a strategy to treat muscular dystrophy and other myopathies.
- Khurana TS, Prendergast RA, Alameddine H, Tome FMS, Fardeau M, Arahata K, Sugita H, & Kunkel LM. (1995) Sparing of extraocular muscles in Duchenne's muscular dystrophy: Role of calcium homeostasis. J. Exp. Med. 182, 467-475
- Neimann CU, Krag TOB & Khurana TS (2000) Identification of genes that are differentially expressed in extraocular and limb muscle. J. Neurol. Sci. 179, 76-84
- Fischer MD, Budak MT, Bakay M, Gorospe JR, Kjellgren D, Pedrosa-Domellof F, Hoffman EP & Khurana TS (2005) Definition of human extraocular muscle allotype by expression profiling. Physiol. Genomics 11, 283-291.
- Khurana TS, Hoffman EP & Kunkel LM. (1990) Identification of a Chromosome 6 encoded Dystrophin-Related Protein J. Biol. Chem. 265, 16717-16720
- Khurana TS, Rosmarin AG, Shang, J., Krag TOB, Das S & Gammeltoft S (1999) Heregulin activates the utrophin promoter via the transcription factor complex GABP a/b. Mol. Biol. Cell. 10, 2075-2086
- Gyrd-Hansen M, Krag TO, Rosmarin AG & Khurana TS (2002) Sp1 and the ets-related transcription factor complex GABP alpha/beta functionally cooperate to activate the utrophin promoter. J. Neurol. Sci. 197, 27-35
- Krag TOB, Bogdanovich S, Jensen CJ, Fischer MD, Hansen-Schwartz J, Javazon EH, Flake AW, Edvinsson L & Khurana TS (2004) Heregulin ameliorates the dystrophic phenotype in mdx mice. Proc. Nat. Acad. Sci. 101, 13856-13860
- Bogdanovich S, Krag TO, Barton ER, Morris LD, Whittemore LA, Ahima RS & Khurana TS (2002) Functional improvement of dystrophic muscle by myostatin blockade. Nature 420, 418-420
- Bogdanovich S, Perkins KJ, Krag TO, Whittemore LA & Khurana TS (2005) Myostatin propeptide-mediated amelioration of dystrophic muscle pathophysiology. FASEB J 19, 543-549
- Khurana TS & Davies KE (2003) Pharmacological Strategies for Muscular Dystrophy. [Review]. Nature Reviews Drug Discovery 2, 379-390
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