Role of KCNB1-Integrin Complexes in neurodevelopment

KCNB1-整合素复合物在神经发育中的作用

• 批准号: 2030348
• 负责人: Federico Sesti
• 金额: $ 92.42万
• 依托单位: Rutgers, The State University of New Jersey-RBHS-Robert Wood
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2030348&HistoricalAwards=false
• 关键词: Role; KCNB1; Integrin; Complexes; neurodevelopment

One of the enduring questions that puzzles neurobiologists is how the brain achieves its highly organized structure. Brain cells (neurons) do not randomly populate the brain; each developing cell undertakes its own journey to occupy a precise position in the brain. When the brain begins to take shape in the early embryo, neurons are generated in a specific zone that they migrate out from, sometimes moving great distances to reach their final position. The newly formed neurons extend thin projections, called axons and dendrites, to form connections with other neurons, giving rise to highly organized networks of interconnected cells. It is well known that neurons are guided by both long-range and short-range chemical clues during their journey, but the migrating neurons also "talk" to each other by exchanging electrical signals. The latter signals also guide neurons' migration choices, and influence which other neurons they ultimately connect with. Previous research shows that neurons use "sensors" (complexes of electrically responsive proteins) to transduce electrical signals into movement and networking responses, but how this happens is currently unknown. This project will elucidate the ways in which these sensors work, and the mechanisms they use to affect the formation of neural circuits in the mammalian brain. In addition to these scientific goals, this project will support a well-established training program for undergraduate and high-school students that exposes them to prominent areas of research, gives them hands-on experience with experimental techniques, and contributes to their successful pursuit of future careers in science. The results of this project are expected to shed new light on a previously unstudied, major aspect of brain circuit development that has important implications for mediating congenital brain malformations and developmental brain disorders. This project deciphers a novel mechanism of cortical development whereby macromolecular complexes formed by voltage-gated potassium channels (KCNB1) and alpha5-beta5 integrins, dubbed IKCs (Integrin-KCNB1-Complexes), transduce the spontaneous electrical activity of emergent neuronal structures into biochemical signals that regulate circuit assembly. It uses a combination of biochemistry, immunohistochemistry, confocal microscopy and animal studies (KI mice harboring defective IKCs) to establish mechanistic links between the developmental processes influenced by IKCs and their resultant circuits and associated behaviors. Understanding how macromolecular complexes consisting of K+ channels and integrins can shape critical neurodevelopmental processes will provide a new window into the molecular mechanisms that underlie the development of neuronal circuits and their associated brain architectures.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

困扰神经生物学家的一个持久问题是大脑如何实现其高度组织化的结构。脑细胞（神经元）并不是随机分布在大脑中的;每个发育中的细胞都有自己的旅程，在大脑中占据一个精确的位置。当大脑在早期胚胎中开始成形时，神经元在特定区域产生，它们从那里迁移出来，有时会移动很远的距离到达最终位置。新形成的神经元延伸出薄的突起，称为轴突和树突，与其他神经元形成连接，产生高度组织化的互连细胞网络。众所周知，神经元在其旅程中受到长距离和短距离化学线索的引导，但迁移的神经元也通过交换电信号相互“交谈”。后一种信号也指导神经元的迁移选择，并影响它们最终与其他神经元连接。先前的研究表明，神经元使用“传感器”（电响应蛋白质的复合物）将电信号转化为运动和网络反应，但目前尚不清楚这是如何发生的。该项目将阐明这些传感器的工作方式，以及它们用于影响哺乳动物大脑神经回路形成的机制。除了这些科学目标，该项目将支持一个完善的本科生和高中生的培训计划，使他们接触到突出的研究领域，给他们实践经验与实验技术，并有助于他们成功地追求未来的科学事业。该项目的结果有望为以前未研究的脑回路发育的主要方面提供新的线索，该方面对介导先天性脑畸形和发育性脑疾病具有重要意义。该项目破译了皮层发育的一种新机制，即由电压门控钾通道（KCNB 1）和α 5-β 5整合素形成的大分子复合物，被称为IKC（整合素-KCNB 1-复合物），将涌现的神经元结构的自发电活动转化为调节电路组装的生化信号。它使用生物化学，免疫组织化学，共聚焦显微镜和动物研究（KI小鼠窝藏缺陷IKCs）的组合，以建立IKCs及其产生的电路和相关行为的影响发育过程之间的机制联系。了解由K+通道和整合素组成的大分子复合物如何塑造关键的神经发育过程，将为神经元回路及其相关脑结构的发展提供一个新的分子机制窗口。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Integrin-KCNB1 potassium channel complexes regulate neocortical neuronal development and are implicated in epilepsy.

• DOI: 10.1038/s41418-022-01072-2
• 发表时间: 2023-03
• 期刊: CELL DEATH AND DIFFERENTIATION
• 影响因子: 12.4
• 作者: Bortolami, Alessandro;Yu, Wei;Forzisi, Elena;Ercan, Koray;Kadakia, Ritik;Murugan, Madhuvika;Fedele, Denise;Estevez, Irving;Boison, Detlev;Rasin, Mladen-Roko;Sesti, Federico
• 通讯作者: Sesti, Federico

Apoptotic cell death in disease-Current understanding of the NCCD 2023.

• DOI: 10.1038/s41418-023-01153-w
• 发表时间: 2023-05
• 期刊: CELL DEATH AND DIFFERENTIATION
• 影响因子: 12.4
• 作者: Vitale, Ilio;Pietrocola, Federico;Guilbaud, Emma;Aaronson, Stuart A.;Abrams, John M.;Adam, Dieter;Agostini, Massimiliano;Agostinis, Patrizia;Alnemri, Emad S.;Altucci, Lucia;Amelio, Ivano;Andrews, David W.;Aqeilan, Rami, I;Arama, Eli;Baehrecke, Eric H.;Balachandran, Siddharth;Bano, Daniele;Barlev, Nickolai A.;Bartek, Jiri;Bazan, Nicolas G.;Becker, Christoph;Bernassola, Francesca;Bertrand, Mathieu J. M.;Bianchi, Marco E.;Blagosklonny, Mikhail V.;Blander, J. Magarian;Blandino, Giovanni;Blomgren, Klas;Borner, Christoph;Bortner, Carl D.;Bove, Pierluigi;Boya, Patricia;Brenner, Catherine;Broz, Petr;Brunner, Thomas;Damgaard, Rune Busk;Calin, George A.;Campanella, Michelangelo;Candi, Eleonora;Carbone, Michele;Carmona-Gutierrez, Didac;Cecconi, Francesco;Chan, Francis K-M;Chen, Guo-Qiang;Chen, Quan;Chen, Youhai H.;Cheng, Emily H.;Chipuk, Jerry E.;Cidlowski, John A.;Ciechanover, Aaron;Ciliberto, Gennaro;Conrad, Marcus;Cubillos-Ruiz, Juan R.;Czabotar, Peter E.;D'Angiolella, Vincenzo;Daugaard, Mads;Dawson, Ted M.;Dawson, Valina L.;De Maria, Ruggero;De Strooper, Bart;Debatin, Klaus-Michael;Deberardinis, Ralph J.;Degterev, Alexei;Del Sal, Giannino;Deshmukh, Mohanish;Di Virgilio, Francesco;Diederich, Marc;Dixon, Scott J.;Dynlacht, Brian D.;El-Deiry, Wafik S.;Elrod, John W.;Engeland, Kurt;Fimia, Gian Maria;Galassi, Claudia;Ganini, Carlo;Garcia-Saez, Ana J.;Garg, Abhishek D.;Garrido, Carmen;Gavathiotis, Evripidis;Gerlic, Motti;Ghosh, Sourav;Green, Douglas R.;Greene, Lloyd A.;Gronemeyer, Hinrich;Haecker, Georg;Hajnoczky, Gyorgy;Hardwick, J. Marie;Haupt, Ygal;He, Sudan;Heery, David M.;Hengartner, Michael O.;Hetz, Claudio;Hildeman, David A.;Ichijo, Hidenori;Inoue, Satoshi;Jaeaettelae, Marja;Janic, Ana;Joseph, Bertrand;Jost, Philipp J.;Kanneganti, Thirumala-Devi;Karin, Michael;Kashkar, Hamid;Kaufmann, Thomas;Kelly, Gemma L.;Kepp, Oliver;Kimchi, Adi;Kitsis, Richard N.;Klionsky, Daniel J.;Kluck, Ruth;Krysko, Dmitri, V;Kulms, Dagmar;Kumar, Sharad;Lavandero, Sergio;Lavrik, Inna N.;Lemasters, John J.;Liccardi, Gianmaria;Linkermann, Andreas;Lipton, Stuart A.;Lockshin, Richard A.;Lopez-Otin, Carlos;Luedde, Tom;MacFarlane, Marion;Madeo, Frank;Malorni, Walter;Manic, Gwenola;Mantovani, Roberto;Marchi, Saverio;Marine, Jean-Christophe;Martin, Seamus J.;Martinou, Jean-Claude;Mastroberardino, Pier G.;Medema, Jan Paul;Mehlen, Patrick;Meier, Pascal;Melino, Gerry;Melino, Sonia;Miao, Edward A.;Moll, Ute M.;Munoz-Pinedo, Cristina;Murphy, Daniel J.;Niklison-Chirou, Maria Victoria;Novelli, Flavia;Nunez, Gabriel;Oberst, Andrew;Ofengeim, Dimitry;Opferman, Joseph T.;Oren, Moshe;Pagano, Michele;Panaretakis, Theocharis;Pasparakis, Manolis;Penninger, Josef M.;Pentimalli, Francesca;Pereira, David M.;Pervaiz, Shazib;Peter, Marcus E.;Pinton, Paolo;Porta, Giovanni;Prehn, Jochen H. M.;Puthalakath, Hamsa;Rabinovich, Gabriel A.;Rajalingam, Krishnaraj;Ravichandran, Kodi S.;Rehm, Markus;Ricci, Jean-Ehrland;Rizzuto, Rosario;Robinson, Nirmal;Rodrigues, Cecilia M. P.;Rotblat, Barak;Rothlin, Carla, V;Rubinsztein, David C.;Rudel, Thomas;Rufini, Alessandro;Ryan, Kevin M.;Sarosiek, Kristopher A.;Sawa, Akira;Sayan, Emre;Schroder, Kate;Scorrano, Luca;Sesti, Federico;Shao, Feng;Shi, Yufang;Sica, Giuseppe S.;Silke, John;Simon, Hans-Uwe;Sistigu, Antonella;Stephanou, Anastasis;Stockwell, Brent R.;Strapazzon, Flavie;Strasser, Andreas;Sun, Liming;Sun, Erwei;Sun, Qiang;Szabadkai, Gyorgy;Tait, Stephen W. G.;Tang, Daolin;Tavernarakis, Nektarios;Troy, Carol M.;Turk, Boris;Urbano, Nicoletta;Vandenabeele, Peter;Vanden Berghe, Tom;Vander Heiden, Matthew G.;Vanderluit, Jacqueline L.;Verkhratsky, Alexei;Villunger, Andreas;von Karstedt, Silvia;Voss, Anne K.;Vousden, Karen H.;Vucic, Domagoj;Vuri, Daniela;Wagner, Erwin F.;Walczak, Henning;Wallach, David;Wang, Ruoning;Wang, Ying;Weber, Achim;Wood, Will;Yamazaki, Takahiro;Yang, Huang-Tian;Zakeri, Zahra;Zawacka-Pankau, Joanna E.;Zhang, Lin;Zhang, Haibing;Zhivotovsky, Boris;Zhou, Wenzhao;Piacentini, Mauro;Kroemer, Guido;Galluzzi, Lorenzo
• 通讯作者: Galluzzi, Lorenzo