Faculty Director: Christopher A. Ross M.D., Ph.D.

Link to PubMed publications for Ross CA
            
分子神经生物学实验室专注于应用生物学技术来研究神经退行性疾病和其他神经精神疾病. 我们对多谷氨酰胺神经退行性疾病如亨廷顿舞蹈病(HD)的发病机制特别感兴趣. 我们使用细胞和转基因小鼠模型来了解这种疾病的发病机制, 同时也帮助开发新的治疗技术. 我们已经将类似的技术应用于帕金森病(PD)的研究. 我们已经确定了几个新的蛋白质参与PD的发病机制, and we have cell and mouse models of the disease. 我们还将类似的技术应用于双相情感障碍和精神分裂症等精神疾病.

The laboratory offers research opportunities to undergraduates, graduate students, postdoctoral fellows and other interested scientists. 该实验室以前的学员在美国和国外都非常成功地发展了独立的研究事业和教职.

Lab Members

Omidreza Firuzi, M.D., Ph.D. - Postdoctoral Fellow
Haibing Jiang, Ph.D. - Postdoctoral Fellow
Yideng Liang, M.D., Ph.D. - Postdoctoral Fellow
Naoki Masuda, Md., Ph.D. - Postdoctoral Fellow
Fred Nucifora, D.O., Ph.D. -Postdoctoral Fellow
Ricky Hischhorn, Ph.D. - Visiting Scientist
Tamara Ratovitski, M.S. - Research Associate
Xiaofang Wang - Mouse Lab Technician
Erin Watkin - Graduate Student
Eileen Kasda - Administrative Manager

Recent Findings and Current Research

Huntington’s Disease

自1993年发现HD基因突变以来，我们的实验室进行了广泛的研究. 该实验室绘制了HD基因及其蛋白产物亨廷顿蛋白的表达模式. 我们发现了第一个与亨廷顿蛋白相互作用的蛋白HAP1. 在实验室进行的研究产生了HD的第一批细胞模型, 发现细胞核是HD毒性的重要部位. In addition, in collaboration with David Borchelt's lab, we generated one of the initial mouse models of HD, 随后在许多HD发病机制和治疗方法的研究中使用. 我们的HD研究利用了巴尔的摩亨廷顿病中心的存在, directed by Dr. Ross, and providing opportunities for clinical correlations.

我们目前的研究集中在发病机制方面，这可能是治疗干预的良好目标. We study posttranslational modification, including proteolytic cleavage of huntingtin, which is believed to be a critical step in pathogenesis, 因为像激酶和蛋白酶这样的酶可以被用作药物的小分子靶向.  我们也研究基因转录，因为药物如HDAC抑制剂可以修饰它. In collaboration with Michelle Poirier’s lab, 我们研究了细胞中产生亨廷顿蛋白聚集体的分子途径, 因为这种聚集途径可能是未来治疗的目标. In collaboration with Wenzhen Duan’s lab, 我们对候选治疗剂进行临床前治疗试验. We also focus on the generation of novel cell and mouse models.

Parkinson’s disease

Parkinson's disease (PD), like HD, involves selective neuronal degeneration, but unlike HD, several genes can cause PD, suggesting the possibility of a pathogenic pathway. Many of our PD studies are conducted as part of the Morris K. Udall Parkinson's Disease Center Center, directed by Ted Dawson. 家族性帕金森病的病因之一涉及α突触核蛋白的突变. 实验室鉴定了α -突触核蛋白的第一个蛋白质相互作用物, which we termed synphilin-1, 并与其他团队合作，证明了路易小体中存在突触1, the pathologic hallmark of PD. 该实验室还开发了PD的α -突触核蛋白细胞模型, likely to be useful for pathologic studies. 我们目前正在研究α -突触核蛋白的聚集途径, in collaboration with Michelle Poirier’s lab, 使用我们开发的细胞模型来测试治疗剂, in collaboration with Wenzhen Duan’s lab.

Familial PD can also be caused by mutations in LRRK2, 其中一种突变(G2019S)是目前已知的导致典型晚发性PD的最常见原因. We have studied LRRK2 in collaboration with Wanli Smith’s lab. We have developed cell models, 并表明突变体LRRK2的细胞毒性依赖于其激酶活性. This makes LRRK2 a very promising therapeutic target. 我们目前正在寻找LRRK2的蛋白相互作用伙伴, developing further cell models, 并开发转基因小鼠模型，以测试激酶活性和蛋白质相互作用的作用, and in order to begin preclinical therapeutic studies. 

Schizophrenia

Similar techniques are now being used to study schizophrenia. Unlike the degenerative diseases, 精神分裂症被认为是由神经发育异常引起的. 候选基因在精神分裂症-1中被破坏(DISC-1)在家族性精神分裂症中发生突变. DISC1 -1与许多参与神经元发育的蛋白质相互作用，DISC1的突变在体外和体内都会干扰神经元的分化和发育. We have developed cell and mouse models using mutant DISC-1. 这些主要是在米哈伊尔·普列特尼科夫的实验室里完成的(详见他的描述). 这些可能阐明精神分裂症的神经发育起源. 需要进一步的研究来确定DISC-1的其他相互作用伙伴, 并确定DISC-1与其他精神分裂症基因和环境风险因素之间的相互作用.   

See also the Department's Schizophrenia Program

Selected Publications

Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron. 2006 Oct 5;52(1):139-53.

Pletnikov MV, Ayhan Y, Xu Y, Nikolskaia O, Ovanesov M, Huang H, Mori, S, Moran TH, 人类DISC1突变体在小鼠体内的诱导表达与大脑和行为异常有关，使人联想到精神分裂症. Mol. Psychiatry 2007.

Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nature Neurosci. 2006 Oct;9(10):1231-3.

Pletnikov MV, Xu Y, Ovanesov MV, Kamiya A, Sawa A, Ross CA. 诱导表达突变体DISC1的PC12细胞模型:异常神经元分化的显性-阴性机制的新证据. Neurosci Res. 2007 Jul;58(3):234-44.

Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18676-81.

Ross CA, Poirier MA. What is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol. 2005 Nov;6(11):891-8.

Wang W, Duan W, Igarashi S, Morita H, Nakamura M, Ross CA. 阻断突变亨廷顿蛋白毒性的化合物使用亨廷顿病神经元细胞模型鉴定. Neurobiol Dis. 2005 Nov;20(2):500-8.

Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nature Medicine 2004 Jul;10 Suppl:S10-7.

Ross CA. 聚谷氨酰胺的发病机制:亨廷顿氏病和相关疾病的统一机制的出现. Neuron.2002 Aug 29;35(5):819-22.

Nucifora FC Jr, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, Takahashi H, Tsuji S, Troncoso J, Dawson VL, Dawson TM, Ross CA. 亨廷顿蛋白和atrophin-1干扰cbp介导的转录导致细胞毒性. Science. 2001 Mar 23;291(5512):2423-8.