3D-NKCC1
3D-NKCC1
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A Marie Skłodowska-Curie Global Fellowship (H2020-MSCA-IF-2018) between US and Italy
A Marie Skłodowska-Curie Global Fellowship (H2020-MSCA-IF-2018) between US and Italy
Interdisciplinary approach to characterize the structure and the ion transport mechanism of NKCC1, a key target for brain disorders.
Interdisciplinary approach to characterize the structure and the ion transport mechanism of NKCC1, a key target for brain disorders.
Cation-coupled chloride cotransporters: chemical insights and disease implications
Cation-coupled chloride cotransporters: chemical insights and disease implications
https://www.cell.com/trends/chemistry/pdf/S2589-5974(21)00119-2.pdf
Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome
Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome
https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00603
A) Summary of the context, overall objectives and conclusions. a) The membrane transporter NKCC1 is involved, with KCC2, in GABAergic transmission modulation by regulating [Cl]i in immature neurons. NKCC1 is implicated in several brain disorders. b) The main objectives of the project are the characterization of the structure (obj1, Year 1) and the function (obj2, Year 2) of NKCC1, using a multidisciplinary approach. c) In conclusions, the insights obtained from the multidisciplinary approach and the broad literature analysis that we carried out helped us in investigating the binding sites of known drugs that modulate NKCC1 activity in order to treat brain disorders effectively and with fewer side effects.
B) Main results achieve so far (Year 1&2), exploitation and dissemination. a) Results obtained during Year 1 and 2 regarding the optimization of the expression and purification, functional assays, optimization parameters for structural biology techniques, and a deep literature analysis on CCC transporter family that has been completed and published as review article on Trends in Chemistry. Additionally the functional characterization of mutated critical key residues in NKCC1 together with the performance of cell-based functional assays with NKCC1 inhibitors. b) Exploitation and dissemination activities.
C) Progress beyond the state of the art and potential impacts. The information from the published review will be relevant for future discovery of NKCC1 complex structures. The progress work in this direction will provide major insights in understanding the modulatory/inhibitory mechanism, to localize the ligand/inhibitor binding site, and to discover new inhibitors, more precise since they will be designed with a structure-based approach. This project will have major impacts on my personal career, as well as at socio-economic and wider level with the discovery of new NKCC1 blockers. Since, so far, no cures are available for neurodevelopmental disorders possibly caused by altered Cl homeostasis, this project could be attractive for pharma companies, and it will potentially have a positive impact on the quality of many patients.
Poster @ 64 Biophysical Society Meeting, BPS 2020
Poster @ 64 Biophysical Society Meeting, BPS 2020
San Diego, USA - February, 2020
San Diego, USA - February, 2020
Talk @ EMBO Workshop 2019 on Tools for structural biology of membrane proteins - Hamburg, GER - October, 2019
Talk @ American Society for Neuroscience Meetings, SFN 2019 - Chicago, US - October, 2019
Public communication activity, to spread the information regarding the project, has been done also through social channels (Twitter and LinkedIn) and a special section in IIT magazine OpenTalk.
I became part of Women In Bio (WIB)-Texas, an organization of volunteers that promotes diversity and inclusion for women in the life sciences. I presented my project in WIB remote/virtual meeting.
YEAR 1 OUTGOING PHASEA) Summary of the context and overall objectives. a) The membrane transporter NKCC1 is involved, with KCC2, in GABAergic transmission modulation by regulating [Cl]i in immature neurons. NKCC1 is implicated in several brain disorders. b) The main objectives of the project are the characterization of the structure (obj1, Year 1) and the function (obj2, Year 2) of NKCC1, using a multidisciplinary approach. The insights obtained will help identify novel drugs that modulate NKCC1 activity in order to treat brain disorders effectively and with fewer side effects.
B) Work performed during Year 1 and main results achieved so far. a) Since NKCC1 structure has been solved so far, this project considered the possibility to focus on the characterization of NKCC1 in complex with bumetanide or newly characterized inhibitors. b) Results obtained so far regard the work on the optimization of the expression and purification, functional assays, optimization parameters for structural biology techniques, and a deep literature analysis on CCC transporter family.
C) Progress beyond the state of the art, expected results and potential impacts. a) The characterization of the complex with NKCC1 will provide major insights regarding different aspects. It will help to understand the modulatory/inhibitory mechanism, to localize the ligand/inhibitor binding site, and to discover new inhibitors, more precise since they will be designed with a structure-based approach. b) This project will have major impacts on my personal career, as well as at socio-economic and wider level with the discovery of new NKCC1 blockers. Since, so far, no cures are available for neurodevelopmental disorders possibly caused by altered Cl homeostasis, this project could be attractive for pharma companies and it will potentially have a positive impact on the quality of many patients.
B) Work performed during Year 1 and main results achieved so far. a) Since NKCC1 structure has been solved so far, this project considered the possibility to focus on the characterization of NKCC1 in complex with bumetanide or newly characterized inhibitors. b) Results obtained so far regard the work on the optimization of the expression and purification, functional assays, optimization parameters for structural biology techniques, and a deep literature analysis on CCC transporter family.
C) Progress beyond the state of the art, expected results and potential impacts. a) The characterization of the complex with NKCC1 will provide major insights regarding different aspects. It will help to understand the modulatory/inhibitory mechanism, to localize the ligand/inhibitor binding site, and to discover new inhibitors, more precise since they will be designed with a structure-based approach. b) This project will have major impacts on my personal career, as well as at socio-economic and wider level with the discovery of new NKCC1 blockers. Since, so far, no cures are available for neurodevelopmental disorders possibly caused by altered Cl homeostasis, this project could be attractive for pharma companies and it will potentially have a positive impact on the quality of many patients.
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