PMID- 34898595
OWN - NLM
STAT- MEDLINE
DCOM- 20220211
LR  - 20220211
IS  - 1553-7358 (Electronic)
IS  - 1553-734X (Print)
IS  - 1553-734X (Linking)
VI  - 17
IP  - 12
DP  - 2021 Dec
TI  - Roles of mTOR in thoracic aortopathy understood by complex intracellular 
      signaling interactions.
PG  - e1009683
LID - 10.1371/journal.pcbi.1009683 [doi]
LID - e1009683
AB  - Thoracic aortopathy-aneurysm, dissection, and rupture-is increasingly responsible 
      for significant morbidity and mortality. Advances in medical genetics and imaging 
      have improved diagnosis and thus enabled earlier prophylactic surgical 
      intervention in many cases. There remains a pressing need, however, to understand 
      better the underlying molecular and cellular mechanisms with the hope of finding 
      robust pharmacotherapies. Diverse studies in patients and mouse models of 
      aortopathy have revealed critical changes in multiple smooth muscle cell 
      signaling pathways that associate with disease, yet integrating information 
      across studies and models has remained challenging. We present a new quantitative 
      network model that includes many of the key smooth muscle cell signaling pathways 
      and validate the model using a detailed data set that focuses on hyperactivation 
      of the mechanistic target of rapamycin (mTOR) pathway and its inhibition using 
      rapamycin. We show that the model can be parameterized to capture the primary 
      experimental findings both qualitatively and quantitatively. We further show that 
      simulating a population of cells by varying receptor reaction weights leads to 
      distinct proteomic clusters within the population, and that these clusters emerge 
      due to a bistable switch driven by positive feedback in the PI3K/AKT/mTOR 
      signaling pathway.
FAU - Estrada, Ana C
AU  - Estrada AC
AUID- ORCID: 0000-0003-0311-1948
AD  - Department of Biomedical Engineering, Yale University; New Haven, Connecticut, 
      United States of America.
FAU - Irons, Linda
AU  - Irons L
AUID- ORCID: 0000-0001-8912-7400
AD  - Department of Biomedical Engineering, Yale University; New Haven, Connecticut, 
      United States of America.
FAU - Rego, Bruno V
AU  - Rego BV
AUID- ORCID: 0000-0002-6315-693X
AD  - Department of Biomedical Engineering, Yale University; New Haven, Connecticut, 
      United States of America.
FAU - Li, Guangxin
AU  - Li G
AD  - Department of Surgery, Yale School of Medicine; New Haven, Connecticut, United 
      States of America.
FAU - Tellides, George
AU  - Tellides G
AUID- ORCID: 0000-0001-7042-8190
AD  - Department of Surgery, Yale School of Medicine; New Haven, Connecticut, United 
      States of America.
AD  - Vascular Biology and Therapeutics Program, Yale School of Medicine; New Haven, 
      Connecticut, United States of America.
FAU - Humphrey, Jay D
AU  - Humphrey JD
AUID- ORCID: 0000-0003-1011-2025
AD  - Department of Biomedical Engineering, Yale University; New Haven, Connecticut, 
      United States of America.
AD  - Vascular Biology and Therapeutics Program, Yale School of Medicine; New Haven, 
      Connecticut, United States of America.
LA  - eng
GR  - P01 HL134605/HL/NHLBI NIH HHS/United States
GR  - R01 HL146723/HL/NHLBI NIH HHS/United States
GR  - U01 HL142518/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20211213
PL  - United States
TA  - PLoS Comput Biol
JT  - PLoS computational biology
JID - 101238922
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - *Aortic Aneurysm/genetics/metabolism
MH  - Humans
MH  - Male
MH  - Mice
MH  - Myocytes, Smooth Muscle/*metabolism
MH  - Signal Transduction/*genetics
MH  - *TOR Serine-Threonine Kinases/genetics/metabolism
PMC - PMC8700007
COIS- The authors have declared that no competing interests exist.
EDAT- 2021/12/14 06:00
MHDA- 2022/02/12 06:00
PMCR- 2021/12/13
CRDT- 2021/12/13 17:38
PHST- 2021/09/27 00:00 [received]
PHST- 2021/11/26 00:00 [accepted]
PHST- 2021/12/23 00:00 [revised]
PHST- 2021/12/14 06:00 [pubmed]
PHST- 2022/02/12 06:00 [medline]
PHST- 2021/12/13 17:38 [entrez]
PHST- 2021/12/13 00:00 [pmc-release]
AID - PCOMPBIOL-D-21-01752 [pii]
AID - 10.1371/journal.pcbi.1009683 [doi]
PST - epublish
SO  - PLoS Comput Biol. 2021 Dec 13;17(12):e1009683. doi: 10.1371/journal.pcbi.1009683. 
      eCollection 2021 Dec.