威廉·布伦肯博士

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研究抽象

The central nervous system (CNS) is organized into ensembles of cells that can be identified by their anatomy and physiology. That is, there are populations of cells with dedicated structure and function. Two fundamental questions about this organization are: (1) what are the mechanisms by which any particular neuronal ensemble establishes its identity and (2) what are the mechanisms by which ensembles find each other and 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 and 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 and the coupled signaling cascades regulate a wide array of developmental events in the eye. Using in vivo and in vitro 实验操作, 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 and photoreceptor synaptic disruption. 视网膜神经节细胞发育不良, Müller cells and 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 understanding 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 and cerebellar development is also disrupted in laminin mutants. Cortical lamination is disrupted in laminin mutant mice, 与放射状胶质组织一起, 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. Indeed, 一个层粘连蛋白基因在人类中的突变, Lamc3, have been shown to cause a very restrictive human lissencephaly.

Our studies demonstrate that laminins and laminin-related genes are critical for normal CNS development, and 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 understanding both normal development and the role of laminins and 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

1. 拉德纳，S，巴诺斯，C.巴切，G., Li, Y.N.亨特·D. D., Brunken W.J. Yee, K.T. β2 and γ3 Laminins Are Critical Cortical Basement Membrane Components: Ablation of Lamb2 and Lamc3 Genes Disrupts Cortical Lamination and Produces Dysplasia. 发育神经生物学, 732013年中期:22961762
2. Gnanaguru G.巴切，G.比斯瓦斯，S.， Pinzón-Duarte, G.A.亨特，D.D., and Brunken W.J., Laminins Containing the β2 and γ3 Chains Regulate Astrocyte Migration And Angiogenesis In the Retina.发展 140: 2050-2061 2013年中期:23571221
3. 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., Maguen 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. 《推荐最近最火的赌博软件》。 8(11): e79632. 2013年中期:24236148
4. Saghizadeh, M.彼凡采娃，我.Hemmati, D.Ghiam C.A.,Brunken W.J., 柳比莫夫，A.V. 促进伤口愈合, kinase and stem cell marker expression in diabetic organ-cultured human corneas upon MMP-10 and cathepsin F gene silencing.投资眼视科学. 54:8172-8180 2013中间值:24255036
5. Ramos, R.L., Siu, N.Y., Brunken W.J., Yee, K.T.洛杉矶，加贝尔.，和B.J. Cellular and Axonal Constituents of Neocortical Molecular Layer Heterotopia. 发育神经科学. 36:477-489 2014中位数:25247689
6. Saghizadeh, M., Dib, C.M., Brunken W.J.柳比莫夫，A.V. Normalization of Wound Healing and Stem Cell Marker Patterns in Organ-Cultured Human Diabetic Corneas by Gene Therapy of Limbal Cells.实验眼研究 129[66-73] 2014年中间值:25446319
7. Kociok N. Crespo-Garcia,年代.， Liang, Y.克莱因，S.V.n伦伯格，C.纽约州莱希哈特(Reichhart.斯科西尔斯基，S.莫里茨，E.麦尔，A., Brunken W.J.施特劳斯，O.科赫，M.乔森，A.M. Lack of netrin-4 modulates pathologic neovascularization in the eye. 科学报告. 6:18828. doi: 10.1038 / srep18828. 2016 pmcid: pmc4702134
8. Biswas年代.巴切，G., Chu, J.亨特，D.D., and Brunken W.J. Laminin-dependent Interaction Between Astrocytes and Microglia: A Role in Retinal Angiogenesis. 美国病理学杂志 187:2112-2127. 2017pmcid: pmc5808181
9. Omar, M.H.坎贝尔-克尔斯克，M.，肖，X.，钟，Q., Brunken W.J.矿工，J.H.格里尔，C.A.科勒斯克，A.J. 中枢神经系统神经元沉积层粘连蛋白 a5来稳定突触. 细胞的报道 21(5): 1281-1292. 2017pmcid: pmc5776391
10. 猎人,维.D.Manglapus, M.K.巴切，G.克劳德皮埃尔，T.多兰，M.W.格苏利，K.A., and Brunken W.J. CNS synapses are stabilized trans-synaptically by laminins and proteins that interact with laminins. J .神经科. 2017年10月12日. doi: 10.1002/cne.24338. [Epub预印]PMID: 29023785