Development of Nanoscale Neuromodulating Platforms

描述（由申请人提供）：视网膜退行性疾病，如年龄相关性黄斑变性，与视网膜杆状和锥状光感受器的功能障碍和退化有关。视杆细胞和视锥细胞近端视网膜神经元的突触后膜受体蛋白在正常功能视网膜的多种化学突触中介导视觉信号的传递，有理由相信，在某些情况下，尽管疾病导致视杆细胞和视锥细胞视觉信号丧失，这些视网膜近端神经元仍保持功能。该项目的长期目标是设计和构建纳米级分子结构，可以选择性地附着在视网膜感光后神经元的特定膜受体的细胞外表面，并通过调节突触后受体对光的反应活性，恢复因感光退行性疾病而受损的视网膜的视觉信号。在本申请中，我们提出了一个针对这一具有挑战性的生物工程目标的5年项目。该研究将涉及分子生物学、有机合成和原型系统的生物物理/电生理分析等紧密结合的研究。所提出的实验的主要焦点是GABAC受体，一种视网膜双极细胞的膜受体蛋白，其已知特性使其非常适合作为模型系统。领导这项研究的将是David R. Pepperberg博士，首席研究员（芝加哥伊利诺伊大学眼科学和视觉科学）；共同研究者Karol S. Bruzik博士（药物化学和生药学，UIC）， Tejal A. Desai博士（生物医学工程，波士顿大学），Jack H. Kaplan博士（生物化学和分子遗传学，UIC）， Brian K. Kay博士（阿贡国家实验室生物科学部），Nalin M. Kumar博士（眼科和视觉科学，UIC）， Guy C. Le Breton博士（药理学，UIC）， Jie Liang博士（生物工程，UIC）， Haohua Qian博士（眼科和视觉科学，UIC），Sandra J. Rosenthal，博士（化学，范德比尔特大学）和Robert F. Standaert，博士（化学，UIC）。摘要：该项目的目标是开发能够恢复光感受器退行性疾病（如年龄相关性黄斑变性）视力的分子结构。这些结构将被设计成附着在病变视网膜的非光感受器细胞上，使这些细胞保持功能，并使这些细胞对光有反应。

DESCRIPTION (provided by applicant): Retinal degenerative diseases such as age-related macular degeneration are associated with dysfunction and deterioration of the rod and cone photoreceptors of the retina. Postsynaptic membrane receptor proteins of retinal neurons proximal to the rods and cones mediate the transmission of visual signals at multiple types of chemical synapses in the normally functioning retina, and there is reason to believe that these proximal retinal neurons in certain cases remain functional despite the disease-induced loss of rod and cone visual signaling. The long-term goal of the proposed project is to design and construct nanoscale molecular structures that can selectively attach to the extracellular face of specific membrane receptors of post-photoreceptor retinal neurons and, by modulating the postsynaptic receptor's activity in response to light, restore visual signaling in retina damaged by photoreceptor degenerative disease. In this application we propose a 5-year project aimed at this challenging bioengineering objective. The research will involve closely integrated studies employing molecular biology, organic synthesis, and biophysical/ electrophysiological analysis of prototype systems. A main focus of the proposed experiments is the GABAC receptor, a membrane receptor protein of retinal bipolar cells whose known properties make it well suited as a model system. Leading the research will be David R. Pepperberg, PhD, Principal Investigator (Ophthalmology and Visual Sciences, Univ. of Illinois at Chicago (UIC)); and Co-Investigators Karol S. Bruzik, PhD (Medicinal Chemistry and Pharmacognosy, UIC), Tejal A. Desai, PhD (Biomedical Engineering, Boston Univ.), Jack H. Kaplan, PhD (Biochemistry and Molecular Genetics, UIC), Brian K. Kay, PhD (Biosciences Division, Argonne National Laboratory), Nalin M. Kumar, PhD (Ophthalmology and Visual Sciences, UIC), Guy C. Le Breton, PhD (Pharmacology, UIC), Jie Liang, PhD (Bioengineering, UIC), Haohua Qian, PhD (Ophthalmology and Visual Sciences, UIC), Sandra J. Rosenthal, PhD (Chemistry, Vanderbilt Univ.), and Robert F. Standaert, PhD (Chemistry, UIC). Lay language summary: The project's objective is to develop molecular structures that can restore vision in photoreceptor degenerative diseases such as age-related macular degeneration. These structures will be designed to attach to non-photoreceptor cells of the diseased retina that remain functional and to make these cells responsive to light.