Neuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes

Summary: Preclinical drug candidates are screened for their ability to ameliorate in vitro neuronal electrophysiology, and go/no-go decisions progress drugs to clinical trials based on population means across cells and animals. However, these measures do not mitigate clinical endpoint risk. Populati...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Sushmita L. Allam, Timothy H. Rumbell, Tuan Hoang-Trong, Jaimit Parikh, James R. Kozloski
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Neuroscience Systems neuroscience In silico biology Science Q
Acceso en línea:	https://doaj.org/article/1c7b6625b6fe493881da67d82223dbf5
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1c7b6625b6fe493881da67d82223dbf5
record_format	dspace
spelling	oai:doaj.org-article:1c7b6625b6fe493881da67d82223dbf52021-11-20T05:09:15ZNeuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes2589-004210.1016/j.isci.2021.103279https://doaj.org/article/1c7b6625b6fe493881da67d82223dbf52021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221012487https://doaj.org/toc/2589-0042Summary: Preclinical drug candidates are screened for their ability to ameliorate in vitro neuronal electrophysiology, and go/no-go decisions progress drugs to clinical trials based on population means across cells and animals. However, these measures do not mitigate clinical endpoint risk. Population-based modeling captures variability across multiple electrophysiological measures from healthy, disease, and drug phenotypes. We pursued optimizing therapeutic targets by identifying coherent sets of ion channel target modulations for recovering heterogeneous wild-type (WT) population excitability profiles from a heterogeneous Huntington’s disease (HD) population. Our approach combines mechanistic simulations with population modeling of striatal neurons using evolutionary optimization algorithms to design ‘virtual drugs’. We introduce efficacy metrics to score populations and rank virtual drug candidates. We found virtual drugs using heuristic approaches that performed better than single target modulators and standard classification methods. We compare a real drug to virtual candidates and demonstrate a novel in silico triaging method.Sushmita L. AllamTimothy H. RumbellTuan Hoang-TrongJaimit ParikhJames R. KozloskiElsevierarticleNeuroscienceSystems neuroscienceIn silico biologyScienceQENiScience, Vol 24, Iss 11, Pp 103279- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neuroscience Systems neuroscience In silico biology Science Q
spellingShingle	Neuroscience Systems neuroscience In silico biology Science Q Sushmita L. Allam Timothy H. Rumbell Tuan Hoang-Trong Jaimit Parikh James R. Kozloski Neuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes
description	Summary: Preclinical drug candidates are screened for their ability to ameliorate in vitro neuronal electrophysiology, and go/no-go decisions progress drugs to clinical trials based on population means across cells and animals. However, these measures do not mitigate clinical endpoint risk. Population-based modeling captures variability across multiple electrophysiological measures from healthy, disease, and drug phenotypes. We pursued optimizing therapeutic targets by identifying coherent sets of ion channel target modulations for recovering heterogeneous wild-type (WT) population excitability profiles from a heterogeneous Huntington’s disease (HD) population. Our approach combines mechanistic simulations with population modeling of striatal neurons using evolutionary optimization algorithms to design ‘virtual drugs’. We introduce efficacy metrics to score populations and rank virtual drug candidates. We found virtual drugs using heuristic approaches that performed better than single target modulators and standard classification methods. We compare a real drug to virtual candidates and demonstrate a novel in silico triaging method.
format	article
author	Sushmita L. Allam Timothy H. Rumbell Tuan Hoang-Trong Jaimit Parikh James R. Kozloski
author_facet	Sushmita L. Allam Timothy H. Rumbell Tuan Hoang-Trong Jaimit Parikh James R. Kozloski
author_sort	Sushmita L. Allam
title	Neuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes
title_short	Neuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes
title_full	Neuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes
title_fullStr	Neuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes
title_full_unstemmed	Neuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes
title_sort	neuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/1c7b6625b6fe493881da67d82223dbf5
work_keys_str_mv	AT sushmitalallam neuronalpopulationmodelsrevealspecificlinearconductancecontrollerssufficienttorescuepreclinicaldiseasephenotypes AT timothyhrumbell neuronalpopulationmodelsrevealspecificlinearconductancecontrollerssufficienttorescuepreclinicaldiseasephenotypes AT tuanhoangtrong neuronalpopulationmodelsrevealspecificlinearconductancecontrollerssufficienttorescuepreclinicaldiseasephenotypes AT jaimitparikh neuronalpopulationmodelsrevealspecificlinearconductancecontrollerssufficienttorescuepreclinicaldiseasephenotypes AT jamesrkozloski neuronalpopulationmodelsrevealspecificlinearconductancecontrollerssufficienttorescuepreclinicaldiseasephenotypes
_version_	1718419528043462656

Neuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes

Ejemplares similares