The central nervous system (CNS) is organized into ensembles of cells that can be identified by their anatomy 和 physiology. That is, there are populations of cells with dedicated structure 和 function. Two fundamental questions about this organization are: (1) what are the mechanisms by which any particular neuronal ensemble establishes its identity 和 (2) what are the mechanisms by which ensembles find each other 和 establish their particular connectivity?

Considerable evidence has shown epigenetic factors to be important in regulating various aspects of development.  The extracellular matrix (ECM) is a rich source of such signals.  Laminins are key elements of the ECM 和 several human diseases are known to result from genetic disruptions in laminin genes or laminin receptor genes, including ocular diseases as well as congenital brain malformations.

We use the vertebrate retina as a "simple" model system to study the role of the ECM in CNS development.  We have shown that laminins are critical to the normal development in the retina. Our data demonstrate that laminins 和 the coupled signaling cascades regulate a wide array of developmental events in the eye. Using in vivo 和 in vitro experimental manipulations, we have shown that deletion of various laminins result in retinal dysgenesis. The abnormalities that are present as a result of these deletions include photoreceptor dysplasia 和 photoreceptor synaptic disruption. Dysgenesis of retinal ganglion cells, Müller cells 和 microglia are also part of the complex phenotype following deletion. In addition to disruptions in the neural organization of the retina, there are profound disruptions in retinal vascular development.  Analyses of these disruptions will contribute significantly to our underst和ing of the pathobiology of several retinal diseases.

Confirming the utility of the retina as a model for the rest of the brain, we have shown that cortical 和 cerebellar development is also disrupted in laminin mutants. Cortical lamination is disrupted in laminin mutant mice, along with radial glial organization, the principle cellular scaffold along which cortical neurons migrate.  In addition, there are ectopic neurons on the surface of the brain. These malformations phenocopy some aspects of human cortical dysgenesis called cobblestone lissencephaly.  事实上, mutations in one laminin gene in humans, Lamc3, have been shown to cause a very restrictive human lissencephaly.

Our studies demonstrate that laminins 和 laminin-related genes are critical for normal CNS development, they implicate the involvement of laminin mutations in a host of human diseases. Our immediate goal is to identify the signaling pathways involved in these processes with the goal of underst和ing both normal development 和 the role of laminins 和 the molecules with which they interact in human disease.  Our long-term goal is to incorporate biologically active molecules into polymers that can be used in neural repair strategies.

最近出版的刊物

Pinzon-Duarte G.戴利，G.，杨，李，亨特，D.D.科赫，M. 和 Brunken W.J. Defective formation of the inner limiting membrane in laminin β2- 和 γ3-null mice produces retinal dysplasia. Investigative Ophthalmology 和 Visual Sciences  51: 1773-1782  2010 PMID: 19907020

Hirrlinger P.G.潘尼克，T.温克勒，美国.克劳德皮埃尔，T.瓦尔什尼，S.舒尔茨，C.Reichenbach, R., Brunken W.J.赫林格，J. Genetic deletion of laminin isoforms β2 和 γ3 induces a reduction in Kir4.1 和 aquaporin-4 expression 和 function in the retina. 《推荐最近最火的赌博软件》. 6: e16106. 2011年编号:21283711

巴拉克. T.关锦华.Y., et al, Recessive LAMC3 mutations cause malformations of the occipital cortical development. 自然遗传学. 43:590-594. 2011年编号:21572413

Saghizadeh, M.苏莱曼尼，S.哈鲁尼安，A.Bhakta, Bhakta, B.特罗扬诺夫斯基，S.M., Brunken W.J.,佩莱格里尼,G.柳比莫夫，A.V. Alterations of epithelial stem cell marker patterns in human diabetic corneas 和 effects of c-met gene therapy. 分子的愿景 17:2177-2190. 2011年编号:21866211

Yebra, M.; diferia.R.蒙哥马利，A.M.凯多，T., Brunken W.J.科赫，M.哈迪曼，G.克里萨，L.和Cirulli, V. Endothelium-Derived Netrin-4 Supports Pancreatic Epithelial Cell Adhesion 和 Differentiation through Integrins α2β1 和 α3β1. 《推荐最近最火的赌博软件》 6:e22750. 2011年编号:21829502

李,Y.N.拉德纳，S.法语，M.M.， Pinzon-Duarte G.戴利，G.H.伯格森，R.E.，科赫，M，和 Brunken W.J.  The γ3 chain of laminin is widely but differentially expressed in murine basement membranes: expression 和 functional studies. 矩阵生物学 31:120-134. 2012年编号:22222602

李,Y.N.， Pinzon-Duarte G.M .帕蒂洛.克劳德皮埃尔，T.科赫，M., Brunken W.J. The Expression And Function Of Netrin-4 In Murine Ocular Tissue. 实验眼研究 96[24-35] 2012年中期:22281059

拉德纳，S，巴诺斯，C.巴切，G.李，Y.N.亨特·D. D., Brunken W.J. Yee, K.T. β2 和 γ3 Laminins Are Critical Cortical Basement Membrane Components: Ablation of Lamb2 和 Lamc3 Genes Disrupts Cortical Lamination 和 Produces Dysplasia. 发育神经生物学, 732013年中期:22961762

Gnanaguru G.巴切，G.比斯瓦斯，S.， Pinzon-Duarte G.A.亨特，D.D., Brunken W.J., Laminins Containing the β2 和 γ3 Chains Regulate Astrocyte Migration And Angiogenesis In the Retina.   发展 140: 2050-2061 2013 PMID: 23571221

Saghizadeh, M.温克勒，M.A.克拉默洛夫，A.A.Hemmati, D.吉安，C.A.迪米特里耶维奇，S.D.萨琳，D., Ornelas. L.H., Brunken W.J.马昆，E.拉比诺维茨，Y.S.斯文森，C.N.，杰尔索瓦，K.柳比莫夫，A.V.  A simple alkaline method for decellularizing human amniotic membrane for cell culture. 科学通报，8(11):992 - 992. 2013.

Saghizadeh, M.彼凡采娃，我.Hemmati, D.吉安，C.A.,  Brunken W.J.柳比莫夫，A.V. (2013) Enhanced wound healing, kinase 和 stem cell marker expression in diabetic organ-cultured human corneas upon MMP-10 和 cathepsin F gene silencing. Investigative Ophthalmology 和 Visual Sciences  54:8172-8180 2013.