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Growth & Development
Bass, J. |
Baumann, G. | Hendrix, MJC | Hirsch, E | Iannaccone, P |
Linzer, D. |
Mauvais-Jarvis, F |
Schnaper, W. |
Tourtellotte, W.
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Joe Bass, M.D., Ph.D.
Department of Medicine
M.D., Ph.D. The Medical College of Pennsylvania
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Cell and Molecular Regulation of Body Weight, Feeding and Metabolism. The focus of our research is on the effect of genetic variation and epigenetic modifiers on insulin signaling and energy homeostasis. We are using molecular genetic approaches including gene targeting and live-cell imaging to elucidate gene and biochemical networks that regulate cell survival, metabolism, and body weight. One goal of these studies is to understand how gene mutations in the insulin receptor (IR) alter its biogenesis, trafficking and cell surface targeting and to use genetic variants of the IR as a desensitizing background in which to uncover additional genes important in blood glucose regulation and neuroendocrine function. More detailed knowledge of these pathways may enable the development of rationally-designed therapies and new preclinical models that will facilitate drug testing and discovery. Our current areas of research are: 1) Function and mechanism of action of glucose-regulated molecular chaperones and heat shock proteins in receptor kinase biogenesis, 2) Tyrosine kinase signaling cascades in metabolic disease and germline mutagenesis models of type 2 diabetes, 3) Mechanisms of obesity, hyperphagia and diabetes in circadian Clock mutant mice.
Together, we now have in place in our laboratory a program that draws on approaches from molecular biology, cell biology and genetics to address fundamental mechanisms in metabolic disease. A considerable strength of this program is the availability of outstanding resources for biomedical research at Northwestern and ENH, including the Targeted Mutagenesis Facility, the Core Biotechnology facilities and extensive support for transgenic technologies and cell imaging. In addition, we have developed several productive collaborative relationships with other research groups both at Northwestern, at other Chicago area medical centers, and several other national medical centers.
Recent Publications:
Bass J, Steiner DF. Insulin receptor folding. In Insulin signaling: from cultured cells to animal models. Harwood Academic Press. Invited review, 2002.
Quing-xin, H, Wilken, J, Nakagawa, S, Ramos, MR, Jia, W, Bass J, and Weiss MA. A divergent invertebrate protein structurally resembles human insulin and activates the human insulin receptor. 2003. Genes and Development 17:826-831 (Perspective p813-818).
Reutrakul S, Hathout EH, Janner D, Hara M, Donfack J, Bass J, Refetoff S. Familial juvenile autoimmune hypothyroidism, pituitary enlargement, obesity, and insulin resistance. Thyroid. 2004 Apr;14(4):311-9.
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Gerhard Baumann, M.D.
Department of Medicine
M.D., University of Basel, Switzerland
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My laboratory is involved in growth hormone (GH) and growth factor research, particularly as it pertains
to the regulation of growth and development in human. Past research has focused on
the molecular heterogeneity of GH and the structure-function relationships of GH variants.
One result of our studies of GH variants in blood was the discovery of the GH
binding protein (GHBP) which represents a circulating extracellular domain of the GH
receptor. Measurement of the GHBP level and its regulation allowed, for the first
time, detailed studies of the function and regulation of the GH receptor in humans in
vivo. Such work had been difficult previously because of the inaccessibility of
tissues bearing GH receptors. In addition to serving as a marker for GH receptor
abundance, the GHBP substantially modulates GH action by altering the in vivo kinetics of
GH and by modulating the interaction of GH with its receptor in tissues.
Several novel insights into the molecular basis of GH resistant and GH hyper-responsive states (Laron and pygmy dwarfism, diabetes,
liver and kidney failure, hypothyroidism, malnutrition, obesity, and aging) have been
gained from the study of the GHBP and GH receptor. Furthermore, the developmental
regulation of GH responsivity throughout life has been delineated through studies of
GHBP/receptor.
Present investigations focus on the expression, tissue distribution and regulation of two splice variants of the GH receptor
in humans, on the relationship between GH receptor/GHBP endowment and somatic
growth/stature, on the mechanism and tissue sites of cleavage of the GHBP from the GH
receptor. In addition, the phenotype and biology of a recently developed GH
receptor/GHBP knockout mouse is being studied in detail.
Another area of research focuses on the GH releasing hormone (GHRH) receptor gene. This was stimulated by the discovery of a
novel severe form of dwarfism in Pakistan that is caused by nonsense mutation in GHRH
receptor gene. We are presently characterizing the genomic organization, structure
and regulation of the human GHRH receptor gene. A potential role of abnormal GHRH
receptor structure or expression in pituitary disease will be investigated.
Recent Publications:
Bauman G 1994 Growth hormone binding protein: State of the art. Endocrinol 141:1-6.
Bauman G 1995 Growth Hormone Binding Protein - Errant Receptor or Active Player? Endocrinology 136:377-378.
Maheshwari H, Sharma L., Bauman G 1996 Decline of Plasma Growth Hormone Binding Protein in Old Age. J Clin Endocrinol Metab 81:995-997.
Morales AJ, Laughlin GA, BŸtzow T, Maheshwari H, Bauman G, Yen SSC 1996 Insulin, Somatotrophic and Luteinizing Hormone Axes
in Lean and Obese Women with Polycystic Ovary Syndrome (PCOS): Common and Distinct Features. J Clin Endocrinol Metab 81:2854-2864.
Keenan BS, Richards GE, Mercado M, Dallas JS, Eakman GD, Bauman G 1996 Androgen Regulation of Growth Hormone Binding Protein (GHBP). Metabolism 45:1521-1526.
Zhou Y, He L, Bauman G, Kopchick JJ 1997 A Mouse Growth Hormone Receptor (mGHR)/Binding Protein (mGHBP) Minigene Directs Expression
of mGHR and mGHBP. J Mol Endocrinol 19:1-13.
Bauman G 1997 Editorial: Growth Without a Pituitary? - Lessons from the Guinea Pig. Endocrinology 138:3575-3576.
Popii V, Baumann G. Laboratory measurement of growth hormone. Clin Chim Acta. 2004 Dec;350(1-2):1-16.
Dschietzig T, Bartsch C, Stangl V, Baumann G, Stangl K. Identification of the pregnancy hormone relaxin as glucocorticoid receptor agonist. FASEB J. 2004 Oct;18(13):1536-8.
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Mary J.C. Hendrix, PhD
Department of Pediatrics
PhD, George Washington University |
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The scientific objectives of the Hendrix laboratory include identifying genes which contribute to cancer metastasis and other related diseases which exhibit similar biological activities. The major goal is to define important structure/function relationships, which provide the biological basis for new therapeutic strategies. Recent studies have generated molecular classification(s) of specific tumors, and have provided new prognostic markers and novel targets for therapeutic intervention. In addition, these studies have identified certain genes that are dysregulated during cancer progression and may also be aberrant during development, resulting in birth defects. Current research activities focus on elucidating how regulatory molecules and phenotype control genes govern cell-to-cell and cell-to-matrix interactions, epithelial/mesenchymal transitions, and motility. Specific projects include signal transduction events initiated by cell adhesion molecules and growth factors; factors regulating interconversion of the tumor cell phenotype; novel three-dimensional analysis of cellular invasion through extracellular matrices; regulation of matrix metalloproteinases by tumor and stromal cell interactions; tumor angiogenesis and vasculogenesis; and the epigenetic role of the microenvironment in determining cell fate and tumor cell plasticity.
Recent Publications:
Rojas JD, Sennoune SR, Maiti D, Bakunts K, Reuveni M, Sanka SC, Martinez GM, Seftor EA, Meininger CJ, Wu G, Wesson DE, Hendrix MJC and Martinez-Zaguilan R. Vacuolar Type H+-ATPases at the plasma membrane regulate pH and cell migration in microvascular endothelial cells. J Cell Physiol, E-Pub, 2006.
Postovit LM, Seftor EA, Seftor REB and Hendrix MJC. Influence of the microenvironment on melanoma cell-fate determination and phenotype. Cancer Research, 66:432-436, 2006.
Postovit LM, Seftor EA, Seftor REB, Hendrix MJC. A Three-dimensional model to study the epigenetic effects induced by the microenvironment of human embryonic stem cells. Stem Cells, 24:501-505, 2006.
Norwood LE, Moss TJ, Margaryan NV, Cook SL, Wright L, Seftor EA, Hendrix MJ, Kirschmann DA, Wallrath LL. A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion. J Biol Chem, 281:18668-18676, 2006.
Bailey CM, Khalkhali-Ellis Z, Seftor EA, Hendrix MJC. The biological functions of maspin. J Cell Physiol, in press, 2006.
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Emmet Hirsch, M.D.
Department of Obstetrics and Gynecology
M.D., Northwestern University |
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Our laboratory primarily investigates infectious and inflammatory processes, with a special emphasis on the underpinnings of preterm labor. Premature birth is the major cause of neonatal morbidity and mortality in the developed world, accounting for at least 75% of neonatal deaths that are not due to congenital malformations. We hope to elucidate the processes by which intrauterine or systemic bacterial infections in pregnancy result in preterm delivery.
We work with both human and animal model systems to try to decipher the signaling pathways by which bacterial infections induce labor (infection is thought to be the cause of up to 30-40% of cases of unexplained preterm birth). Using mouse models and data and tissue samples obtained from pregnant women, members of the lab are investigating the roles of the uterus, fetus and placenta in this process. Ongoing work includes the use of mutant animals with altered expression of candidate critical factors (knockout and transgenic mice). A DNA microarray chip experiment is being used to characterize on a global scale the maternal and fetal signals important for preterm labor. This technology will help generate large and unique gene expression databases of laboring human and mouse pregnancy tissues.
Recent studies in our lab have focused on the roles of inflammatory mediators such as interleukin 1 (IL-1), tumor necrosis factor (TNF), prostaglandins and members of the innate immune system’s recognition pathway for bacterial pathogens (toll-like receptors - TLRs - and their downstream mediators). Data from the lab were the first to demonstrate that interleukin 1 is not an essential mediator of bacterially induced preterm labor, although it plays a necessary overlapping role together with TNF. Important distinctions between fetal and maternal gene expression have led to novel insights regarding the relative roles of the fetus and mother in initiating labor. Other studies have shown that the expression of prostaglandins (long considered the central downstream player in generating uterine contractions) is regulated via altered degradation rather than altered production. We have also demonstrated that TLR4 signaling is necessary for E. coli-induced preterm labor in the mouse. Ongoing in vivo and in vitro experiments explore the potential roles of other TLRs and of dominant-negative fusion proteins generated in the lab to interrupt the cascade leading from infection to expression of inflammatory markers, to expression of labor-specific genes, to delivery.
Recent Publications:
Hirsch E, Mehta SP, Blanchard RK. Differential fetal and maternal contributions to the cytokine milieu in a murine model of infection-induced preterm birth. Am J Obstet Gynecol (1999) 180(2 Pt 1): 429-434.
Irikura VM, Hirsch E, Hirsh D. Effects of interleukin 1 receptor antagonist overexpression on infection by Listeria monocytogenes. Infect Immun (1999) 67: 1901-1909.
Mussalli GM, Blanchard RK, Brunnert SR, Hirsch E. Inflammatory cytokines in a murine model of infection-induced preterm labor: Cause or effect? J Soc Gynecol Invest (1999) 6:188-195.
Muhle RA, Pavlidis P, Grundy WN, Hirsch E. A high throughput study of gene expression in preterm labor with a subtractive microarray approach. Am J Obstet Gynecol (2001) 185:716-724.
Hirsch E, Wang H. The molecular pathophysiology of bacterially induced preterm labor: Insights from the murine model. J Soc Gynecol Investig. 2004 Apr;12(3):145-5.
Yoshimura K, Hirsch E, Kitano R, Kashimura M. Cervical varix accompanied by placenta previa in twin pregnancy. : J Obstet Gynaecol Res. 2004 Aug;30(4):323-5.
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Philip M. Iannaccone, MD, PhD
Department of Pediatrics
MD, SUNY Upstate Medical Center
PhD, University of Oxford (Lincoln Coll.) |
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In my early research career I established the clonal nature of chemically induced tumors. Later my lab established that exposure to direct acting mutagenic agents at preimplantation stages of development caused birth defects, poor implantation, greatly increased perinatal mortality and increased mortality throughout life. We established that endometrial cells had inducible phase I metabolizing activity, that TCDD was a powerful activator of AHH activity in endometrial cells and that estrogen inhibited TCDD's ability to induce this activity in these cells. We showed that the HPV genome was sufficient to induce tumorigenesis in transgenic mice. We established the nature of the embryonic lethality of null mutations in a gene that is now known as nodal and established its critical role in mesoderm formation.
We are currently working on two major projects. The first is designed to understand the role of the GLI family of transcription factors in normal development and disease. These genes code for proteins that reside in the cytoplasm but mediate the Sonic hedgehog signal transduction pathway following translocation to the nucleus. They regulate both cellular differentiation and proliferation. To fully understand the mechanism of their actions we have pursued and continue to study the genetic regulation of the genes at both transcriptional and post-transcriptional levels. We have established protein domains that are sufficient to regulate target genes and we are working to understand both co-activators in the process and biochemical mechanisms behind it. We very much want to pursue these mechanisms at a structural level. We have identified major downstream targets in a transcription factor dependent manner using high throughput gene expression profiling. We have shown that the protein Quaking binds the 3’UTR of the GLI1 RNA and represses translation of the GLI1 protein. The disruption of the pathway is associated with basal cell carcinoma of the skin, the most common cancer of man, prostate cancer, medullobalstoma and sarcomas. The pathway when under-active is associated with severe birth defects. In collaboration with Dave Walterhouse and Marilyn Lamm we have described the role of Sonic hedgehog and GLI in prostate development. Understanding the biochemical mechanisms behind the associations between the GLI family of genes and human disease could have a major public health impact.
The second project grew from work of my lab more than 20 years ago showing that chemically induced tumors were clonal in origin using mouse genetic chimeras. We developed new methodologies to establish that preneoplastic lesions were also clonal and thus the earliest events in carcinogenesis were stochastic and arose in single cells. This was done in rat chimeras where cell lineage could be established microscopically, a system that my lab developed. I observed that mosaic pattern within the tissues of these animals was prototypical and hence both conserved and regulated. Since these patterns were largely the result of cell division patterns we ascertained that they could be used to discern repetitive cell division rule sets in organ development. I went on to formally prove the patterns to be fractal, a prediction of repetitive cell division rules. My lab established computer models of this process and we continue to study the dynamics of cell division during organ development in this way. In an attempt to use increasingly robust markers of mosaic pattern some years ago we began to explore germ line modification of the rat. We continue to study somatic cell nuclear transfer in the rat, embryonic stem cells and the role of signaling pathways in the regulation of stem cell proliferation.
Recent Publications:
Iannaccone, P.M., Bader, M., and Galat, V. (2002). Cloning of rats. In "Principles of Cloning" (J. Cibelli, R. P. Lanza, K. H. S. Campbell, and M. D. West, Eds.), pp. 403-415. Academic Press, San Diego.
Zhou, Y., Galat, V., Garton, R., Taborn, G. and Iannaccone, P. Two-phase chemically defined culture system for preimplantation rat embryos. Genesis: J. of Genetics and Development 36:129-133, 2003.
Walterhouse, D., Lamm, M.L.G., Villavicencio, E., and Iannaccone, P.M. Emerging roles for Hedgehog-Patched- GLI signal transduction in reproduction. Biol. of Reprod. 69:8-14 (2003).
Yang, X.Z., Han, M-S., Niwa, K., and Iannaccone, P.M. Factors Required during Preculture of Rat Oocytes Soon after Sperm Penetration for Promoting Their Further Development in a Chemically Defined Medium. J. Repro. Devel. 50:533-40 (2004).
Lakzia, O., Frater, L., Yoo, Y., Villavicencio, E., Walterhouse, D.O., Goodwin, E.B. and Iannaccone, P.M.. STAR Proteins Quacking-6 and GLD-1 Regulate the Translation of Homologues GLI1 and Tra-1 Through a Conserved RNA 3'UTR Based Mechanism. Dev. Biol. 287:98-110. Epub 2005 Sep 29 (2005).
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Daniel I.H. Linzer, Ph.D.
Department of Biochemistry, Molecular Biology, and Cell Biology
Ph.D., Princeton University
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The placenta mediates implantation of the embryo into the maternal uterus; it forms a barrier
to the maternal immune system and to the passage of certain compounds into the fetus; it
provides a vascular system for the exchange of nutrients and waste products between the
mother and the fetus; and it synthesizes hormones that act on the mother, the fetus, and
the placenta. In many mammalian species, hormones closely related to prolactin are
produced by the placenta. In the mouse, these placental proteins include placental
lactogen I, placental lactogen II, proliferin, and proliferin-related protein. Placental
lactogens I and II each bind to the prolactin receptor. During early pregnancy, prolactin
is the principal hormone that binds to the prolactin receptor, but at mid-pregnancy
prolactin levels decline and placental lactogen I appears at high levels; later in
pregnancy, placental lactogen I is replaced in the circulation by placental lactogen II.
We are studying the placental- and temporal-specific synthesis of these hormones as a
means of following trophoblast differentiation and placental development. Another area of
study is the expression and signal transducing action of the prolactin receptor, the
target of these hormones.
We have recently demonstrated that proliferin stimulates angiogenesis, whereas proliferin-related protein
inhibits this process. Proliferin, which is secreted earlier in pregnancy than
proliferin-related protein, may be responsible for stimulating the migration of blood
vessels in the uterus towards the placenta. Proliferin-related protein may then prevent
the reestablishment of intact vessels, enabling the placental trophoblast cells to come
into direct contact with maternal blood. It is also possible that proliferin-related
protein restricts blood vessel growth, thereby limiting the growth and invasiveness of the
placenta. Current efforts are directed at understanding the molecular mechanisms by which
these hormones act.
Recent Publications:
Thadani PV, Strauss JF 3rd, Dey SK, Anderson VM, Audus KL, Coats KS, Cross JC, Erlebacher A, Ganapathy V, Linzer DI, Miller RK, Novak DA, Rapaka RS, Sadovsky Y, Salafia CM, Soares M, Unadkat J. National Institute on Drug Abuse Conference report on placental proteins, drug transport, and fetal development.Am J Obstet Gynecol. 2004 Dec;191(6):1858-62. Review.
Zhou B, Kong X, Linzer DI. Enhanced Recovery from Thrombocytopenia and Neutropenia in Mice Constitutively Expressing a Placental Hematopoietic Cytokine. Endocrinology. [Epub 2004 Sep 16]
Soloveva V, Linzer DI. Differentiation of placental trophoblast giant cells requires downregulation of p53 and Rb. Placenta. 2004 Jan;25(1):29-36.
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Franck Mauvais-Jarvis, MD,PhD
Endocrinology
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Mouse genetics is a powerful tool to uncover new paradigms in the regulation of energy metabolism. It is also one of the best available models to study the genetic and environmental cause, and therapeutic perspectives for diabetes and obesity. Our laboratory focuses on identifying the cellular and molecular mechanisms by which reproductive hormones program energy metabolism and influence the risks of obesity and diabetes. We use genetic, physiological, molecular, and pharmacological tools to study mice with conditional gene targeting of the estrogen and androgen receptors as well as genetically modified cell culture models in highly controlled environments. Our goal 1) is to obtain a better understanding of the biological processes at the root of diabetes and obesity, from the molecular standpoint to the population level, 2) to determine how to modulate sex steroid actions in a tissue-specific manner in order to have a therapeutic impact on diabetes and obesity in a gender-neutral or gender-specific manner.
Major areas of research in our Laboratory are:
- Molecular genetics of gender dimorphism in human diabetes and obesity
- Mechanisms of estrogen and androgen regulation of pancreatic islet biology and insulin production
- Mechanisms of estrogen and androgen regulation of adipose tissue development biology, insulin sensitivity
- Programming and genetic regulation of energy metabolism by estrogens and androgens in males and females
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H. William Schnaper, M.D.
Department of Pediatrics
M.S., University of Maryland
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The
interests of our laboratory center upon the regulation of endothelial cell angiogenic
activity by estrogen. We have determined that estrogen augments human endothelial cell
migration, proliferation, attachment to extracellular matrix proteins, and differentiation
into capillary-like structures in vitro. In a murine in vivo model, estrogen
augments actual angiogenesis induced by basic fibroblast growth factor (bFGF), a major
participant in angiogenic pathways. These activities may play an important role in growth
of decidual tissue during the menstrual cycle and in placental development during
gestation.
We have identified a
functional estrogen receptor in human endothelial cells that appears to modulate cell
function via a classical steroid hormone receptor mechanism. In one model system, we have
determined that estrogen stimulates delayed induction of mitogen-activated protein kinase
(ERK 1/2) activity, probably via an autocrine loop involving bFGF. A major goal of the
laboratory is to identify upstream and downstream elements of this signaling cascade and
to determine the role each plays in regulating endothelial cell activity.
Recent Publications:
Runyan CE, Schnaper HW, Poncelet AC. The role of internalization in TGF-beta 1-induced Smad2 association with SARA and Smad2-dependent signaling in human mesangial cells. J Biol Chem. 2004 Dec 21; PMID: 15613484
Hayashida T, Schnaper HW. High ambient glucose enhances sensitivity to TGF-beta1 via extracellular signal--regulated kinase and protein kinase Cdelta activities in human mesangial cells. J Am Soc Nephrol. 2004 Aug;15(8):2032-41.
Runyan CE, Schnaper HW, Poncelet AC. The phosphatidylinositol 3-kinase/Akt pathway enhances Smad3-stimulated mesangial cell collagen I expression in response to transforming growth factor-beta1. J Biol Chem. 2004 Jan 23;279(4):2632-9.
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Warren G. Tourtellotte, M.D., Ph.D.
Department of Pathology
M.D., Ph.D., The University of Iowa College of Medicine
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Complex cellular processes such as growth and
differentiation are influenced by epigenetic factors such as cytokines, trophic factors
and cell-cell contact. These factors exert their control by activating cellular signal
transduction pathways that alter gene expression via transcriptional regulators. We are
studying a family of immediate early genes that behave as transcriptional regulators known
as Egr1, Egr2, Egr3 and Egr4. Our research focuses on their function during development of
the mammalian nervous system. We and others have discovered that these transcription
factors regulate a variety of developmental processes including hindbrain organization,
peripheral nerve myelination, male and female fertility, and muscle mechanoreceptor
development involved in limb position perception (proprioception).
We are particularly interested in understanding the signal transduction processes involved
in the activation of Egr genes, the specific target genes and developmental pathways that
they regulate, and identifying biological processes where Egr transcription factors have
redundant functions with one another. We use a variety of contemporary approaches to
functional genomics that are guided by phenotypes revealed in our engineered (mutant
transgenic) mice. Some of the techniques utilized in the laboratory include mouse
transgenics (knockout, knockin and transgenic), recombinant virus (adenovirus and
retrovirus) production for use as in vivo and in vitro transgenic vectors, gene expression
analysis including real-time PCR (Taqman) and microarray technologies. There are many
opportunities in the laboratory to pursue molecular neurobiology research related to gene
regulation in the mammalian nervous system.
Recent Publications:
Tourtellotte WG, Nagarajan R, Bartke A,
Milbrandt J: Functional compensation by Egr4 in Egr1-dependent luteinizing hormone
regulation and Leydig cell steroidogenesis. Mol. Cell. Biol., 20, 5261-5268 (2000).
W.G. Tourtellotte, R. Nagarajan, A. Auyeung,
C. Mueller and J. Milbrandt (1999) Infertility associated with incomplete spermatogenic
arrest and oligozoospermia in Egr4 deficient mice. Devel. 126: 5061-5071.
Whitehead J, Keller-Peck C, Kucera J, Tourtellotte WG. Glial cell-line derived neurotrophic factor-dependent fusimotor neuron survival during development. Mech Dev. 2005 Jan;122(1):27-41.
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