Department of Pharmacology Faculty

Rajendra S. Raghow, Ph.D.

Rajendra S. Raghow, Ph.D.

Professor
Room BE139 Veterans Affairs Medical Center
Email: rraghow@uthsc.edu
Phone: 901-523-5990 ext. 7634
Fax: 901-448-7300

Education

  • Punjab University, Chandigarh, India B.Sc. 1968 Biology
  • Punjab University, Chandigarh, India M.Sc. 1969 Biology
  • Australian National University, Canberra, Australia Ph.D. 1974 Biochemistry
  • St. Jude Children's Research Hospital, Memphis, TN Post Doc. 1977-78 Molecular Biology

Research Interests

Using cellular, biochemical and molecular biological approaches and transgenic technologies, we are studying the regulatory mechanisms by which components of extracellular matrix (e.g. collagen and fibronectin), cytokines (e.g. transforming growth factor bs and bone morphogenetic proteins) and autocoids (prostaglandins and other arachidonic acid metabolites) orchestrate post-inflammatory wound healing, tissue regeneration and organogenesis. The long-term goal of our studies is to define the precise cellular and molecular interactions that activate Msx class of homeodomain containing genes and regulation of developmental and regenerative tissue remodeling by prostaglandins.

The post-inflammatory wound healing and tissue regeneration and repair in the adult seem to recapitulate a number of events commonly encountered in the developing embryo. A precise regulation of cellular migration, proliferation, apoptosis and differentiation is a prerequisite for embryo development as well as tissue repair. We wish to unravel the mechanistic interactions by which genes encoding signaling molecules, developmental morphogens, growth and survival factors, cell adhesion molecules and transcription factors determine dictate the final outcome of these phenomena. The following projects currently being investigated in our laboratory:

Regulation of Msx1/Msx3 gene expression

Members of the Msx family of genes, particularly Msx1 and Msx2, play a crucial role in the program of craniofacial morphogenesis. Mice lacking Msx1 are born with cleft palates, deformed alveolar mandibles and maxillary bones, and no teeth. In humans, mutations of Msx1 and Msx2 genes cause congenital tooth agenesis and craniosynostosis, respectively. A partial or complete absence of Msx1 gene expression leads to severe developmental anomalies. Therefore, elucidation of the mechanisms that dictate timing, tissue-specificity and the extent of Msx1 gene expression are critical to understanding the molecular basis of craniofacial development.

We are studying putative cis-acting elements of murine Msx1 gene that activate its transciption in the neural tube, limb buds and craniofacial primordia of the developing mouse embryos. We have discovered that a -165/+106bp Msx1 promoter efficiently drives heterologous gene (b-galactosidase) expression in the craniofacial tissues of transgenic mice. The cis-acting elements of the craniofacial-specific Msx1 promoter and enhancer are being dissected by site-specific mutagenesis and by assessing functional consequences of such alterations for spatio-temporal activation of Msx1 promoter/enhancer-driven reporter genes in vivo. Our goal is to characterize and clone cDNAs that encode trans-acting factors that activate Msx1/3 promoter/enhancer and decipher their mechanism of action.

Elucidating the pathophysiological roles of prostaglandins

In addition to regulating hemodynamics of the kidney vasculature and salt and water homeostasis in the adult, prostaglandins (PGs) are involved in the development and maturation of the embryonic kidney. PGs are produced via a rate limiting conversion of arachidonic acid (AA) into PGH2 by either of two cyclooxygenases, COX-1 and COX-2, encoded by unique genes, ptgs-1 and ptgs-2, respectively. The ptgs-1 gene encodes the constitutively active enzyme, COX-1 while ptgs-2 (COX-2) is highly induced in response to inflammatory and mitogenic stimuli. A comparison of mice that are genetically deficient in Cox-1 or Cox-2 suggests that the isoforms exert unique as well common effects on the processes of carcinogenesis, inflammation, gastric ulceration and female reproductive functions. The deficiency of Cox-2 (in contrast to Cox-1) leads to abnormal development of kidney and female sterility. The COX-2 ablated mice are born with renal dysplasia and their kidneys contain fewer nephrons and an abundance of immature glomeruli and undifferentiated mesenchyme. The COX-2 null mice ultimately succumb to renal failure. We wish to understand how COX-2 gene ablation alters the cellular and molecular program of nephrogenesis.

The normal kidney develops via a highly coordinated, multi-step process of reciprocal induction between ureteric bud and metanephric mesenchyme. We hypothesize that the kidneys of COX-2 -/- mice elicit a compensatory program of signaling and gene expression. Therefore, the mechanisms of defective kidney development in the COX-2 ablated mice may be elucidated by identifying the candidate genes by genome-wide screening and analyzing the mechanism of their action in vivo and in vitro. We are in the process of identifying and clone cDNAs that are preferentially expressed in the kidneys of wild type and COX-2-/- mice by the methods of differential display, and (ii) by competitive hybridization to mouse-specific cDNA microarrays. We will compare the cell-specific and temporal patterns of expression of the candidate genes in the developing kidneys of the Cox-2 deficient and wild type mice by RT-PCR, in situ hybridization and in situ immuno-cytochemical methods. We plan to alter expression of key genes in the wild type and Cox-2-/- kidneys to elucidate their mechanistic role in the process of nephrogenesis. We will examine the consequences of Cox-2 selective inhibitors on renal development and carry out experiments to potentially rescue the renal pathology of Cox-2 deficient mice.

Laboratory Roster

Publications

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