Role of mTOR, a Component of the Akt Pathway, in Regulating Cardiac Function View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2004-2015

FUNDING AMOUNT

2975056 USD

ABSTRACT

PROJECT SUMMARY The overall aim of this project is to uncover the role of the mTOR (mammalian target of rapamycin) pathway and its relationship to p53 during normal and heart failure (HF) conditions. Myocardial mTOR activity, while increased in the early phases of pressure overload hypertrophy, eventually decreases when compensated hypertrophy switches to decompensation, ending in frank HF. We hypothesized therefore that mTOR and its downstream substrates are central in this process. For proving this, we therefore generated an inducible and cardiac-specific mouse model defective in mTOR (mTOR-cKO). We found that upon loss of mTOR, mice developed dilated heart phenotype that progressed rapidly to death. Markers of autophagy and apoptosis increased significantly; importantly, the tumor suppressor gene p53 significantly accumulated in the heart of mTOR KO mice; moreover, there was a remarkable myocardial accumulation of active 4E-BP1, a downstream member of the mTOR pathway which negatively controls mRNA translation in its dephosphorylated form and a major substrate of TORC-1, one of the two mTOR kinase multiprotein complexes. We found that acumulation of dephosphorylated 4E-BP1 is a feature of HF of diverse etiologies, and thus might represent a common mechanism underlying this state. We also found that deleting 4E-BP1 in mice determines a very significant improvement of cardiac function and survival in the context of cardiac mTOR KO. In other cellular systems, 4E-BPs were shown to regulate p53 protein levels. The specific aims of this project therefore are 1) to determine the relative role of apoptosis and autophagy in mTOR-defective HF and in particular the role of the key gene p53 and 2) determine the role of 4E-BPs in mTOR-dependent HF as well as the reciprocal control between 4E-BPs and p53. These tasks will be accomplished through cross-breeding experiments of mTOR-cKO mice with strains in which Atg5, a gene critical for autophagy, or Nix, a gene critical for apoptosis, are deleted. Also, the role of p53 will be assessed by crossing our model with mice with p53-floxed alleles. Gene expression and proteomic studies will be conducted with the aim to identify genes critical for mTOR-cKO HF. The involvement of 4E-BPs in regulating cardiac function as well as p53 levels will be addressed by crossing mTOR-cKO with double 4E-BP1/4E-BP2 KO mice and by studying the role of p53 in regulating 4E-BP1 expression. Results of our research will assess the relative and reciprocal role of mTOR/4E-BP1 and p53 in controlling cardiac function in the normal and diseased heart, opening the possibility to interfere with these molecules for therapeutic purposes. More... »

URL

http://projectreporter.nih.gov/project_info_description.cfm?aid=8585080

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/2211", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "type": "DefinedTerm"
      }
    ], 
    "amount": {
      "currency": "USD", 
      "type": "MonetaryAmount", 
      "value": "2975056"
    }, 
    "description": "PROJECT SUMMARY The overall aim of this project is to uncover the role of the mTOR (mammalian target of rapamycin) pathway and its relationship to p53 during normal and heart failure (HF) conditions. Myocardial mTOR activity, while increased in the early phases of pressure overload hypertrophy, eventually decreases when compensated hypertrophy switches to decompensation, ending in frank HF. We hypothesized therefore that mTOR and its downstream substrates are central in this process. For proving this, we therefore generated an inducible and cardiac-specific mouse model defective in mTOR (mTOR-cKO). We found that upon loss of mTOR, mice developed dilated heart phenotype that progressed rapidly to death. Markers of autophagy and apoptosis increased significantly; importantly, the tumor suppressor gene p53 significantly accumulated in the heart of mTOR KO mice; moreover, there was a remarkable myocardial accumulation of active 4E-BP1, a downstream member of the mTOR pathway which negatively controls mRNA translation in its dephosphorylated form and a major substrate of TORC-1, one of the two mTOR kinase multiprotein complexes. We found that acumulation of dephosphorylated 4E-BP1 is a feature of HF of diverse etiologies, and thus might represent a common mechanism underlying this state. We also found that deleting 4E-BP1 in mice determines a very significant improvement of cardiac function and survival in the context of cardiac mTOR KO. In other cellular systems, 4E-BPs were shown to regulate p53 protein levels. The specific aims of this project therefore are 1) to determine the relative role of apoptosis and autophagy in mTOR-defective HF and in particular the role of the key gene p53 and 2) determine the role of 4E-BPs in mTOR-dependent HF as well as the reciprocal control between 4E-BPs and p53. These tasks will be accomplished through cross-breeding experiments of mTOR-cKO mice with strains in which Atg5, a gene critical for autophagy, or Nix, a gene critical for apoptosis, are deleted. Also, the role of p53 will be assessed by crossing our model with mice with p53-floxed alleles. Gene expression and proteomic studies will be conducted with the aim to identify genes critical for mTOR-cKO HF. The involvement of 4E-BPs in regulating cardiac function as well as p53 levels will be addressed by crossing mTOR-cKO with double 4E-BP1/4E-BP2 KO mice and by studying the role of p53 in regulating 4E-BP1 expression. Results of our research will assess the relative and reciprocal role of mTOR/4E-BP1 and p53 in controlling cardiac function in the normal and diseased heart, opening the possibility to interfere with these molecules for therapeutic purposes.", 
    "endDate": "2015-11-30T00:00:00Z", 
    "funder": {
      "id": "https://www.grid.ac/institutes/grid.279885.9", 
      "type": "Organization"
    }, 
    "id": "sg:grant.2540161", 
    "identifier": [
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "2540161"
        ]
      }, 
      {
        "name": "nih_id", 
        "type": "PropertyValue", 
        "value": [
          "R01HL078797"
        ]
      }
    ], 
    "inLanguage": [
      "en"
    ], 
    "keywords": [
      "mice", 
      "survival", 
      "task", 
      "Akt pathway", 
      "frank HF", 
      "heart failure", 
      "common mechanism", 
      "model", 
      "downstream substrates", 
      "tumor suppressor gene p53", 
      "mammalian target", 
      "autophagy", 
      "4E-BPs", 
      "cardiac-specific mouse model", 
      "rapamycin", 
      "heart", 
      "role", 
      "state", 
      "early phase", 
      "decompensation", 
      "pathway", 
      "mTOR KO mice", 
      "loss", 
      "dephosphorylated forms", 
      "Regulating Cardiac Function", 
      "mTOR-dependent HF", 
      "p53", 
      "research", 
      "aim", 
      "cross", 
      "pressure overload hypertrophy", 
      "specific aim", 
      "mTOR-cKO HF", 
      "alleles", 
      "acumulation", 
      "process", 
      "strains", 
      "possibility", 
      "mTOR", 
      "mTOR kinase multiprotein complexes", 
      "results", 
      "major substrate", 
      "4E-BP", 
      "BP2 KO mice", 
      "diverse etiologies", 
      "mTOR-cKO mice", 
      "apoptosis", 
      "cardiac function", 
      "gene expression", 
      "4E-BP1/4E", 
      "TORC-1", 
      "mTOR-cKO", 
      "molecules", 
      "4E-BP1 expression", 
      "conditions", 
      "downstream members", 
      "therapeutic purposes", 
      "Atg5", 
      "involvement", 
      "remarkable myocardial accumulation", 
      "4E-BP1", 
      "relationship", 
      "key gene p53", 
      "genes", 
      "mTOR/4E-BP1", 
      "markers", 
      "diseased heart", 
      "other cellular systems", 
      "Myocardial mTOR activity", 
      "mTOR pathway", 
      "experiments", 
      "significant improvement", 
      "project summaries", 
      "death", 
      "cardiac mTOR KO", 
      "reciprocal control", 
      "Nix", 
      "hypertrophy switches", 
      "mTOR-defective HF", 
      "reciprocal role", 
      "mRNA translation", 
      "context", 
      "p53 levels", 
      "overall aim", 
      "proteomic studies", 
      "features", 
      "p53 protein levels", 
      "relative roles", 
      "components", 
      "project", 
      "dilated heart phenotype"
    ], 
    "name": "Role of mTOR, a Component of the Akt Pathway, in Regulating Cardiac Function", 
    "recipient": [
      {
        "id": "https://www.grid.ac/institutes/grid.266100.3", 
        "type": "Organization"
      }, 
      {
        "affiliation": {
          "id": "https://www.grid.ac/institutes/grid.266100.3", 
          "name": "UNIVERSITY OF CALIFORNIA SAN DIEGO", 
          "type": "Organization"
        }, 
        "familyName": "KNOWLTON", 
        "givenName": "KIRK U", 
        "id": "sg:person.01321112106.55", 
        "type": "Person"
      }, 
      {
        "member": "sg:person.01321112106.55", 
        "roleName": "PI", 
        "type": "Role"
      }
    ], 
    "sameAs": [
      "https://app.dimensions.ai/details/grant/grant.2540161"
    ], 
    "sdDataset": "grants", 
    "sdDatePublished": "2019-03-07T11:58", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com.uberresearch.data.processor/core_data/20181219_192338/projects/base/nih_projects_10.xml.gz", 
    "startDate": "2004-12-01T00:00:00Z", 
    "type": "MonetaryGrant", 
    "url": "http://projectreporter.nih.gov/project_info_description.cfm?aid=8585080"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/grant.2540161'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/grant.2540161'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/grant.2540161'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/grant.2540161'


 

This table displays all metadata directly associated to this object as RDF triples.

135 TRIPLES      19 PREDICATES      113 URIs      105 LITERALS      5 BLANK NODES

Subject Predicate Object
1 sg:grant.2540161 schema:about anzsrc-for:2211
2 schema:amount Na9bba20b790f4ab5bd677cbc2d571ea1
3 schema:description PROJECT SUMMARY The overall aim of this project is to uncover the role of the mTOR (mammalian target of rapamycin) pathway and its relationship to p53 during normal and heart failure (HF) conditions. Myocardial mTOR activity, while increased in the early phases of pressure overload hypertrophy, eventually decreases when compensated hypertrophy switches to decompensation, ending in frank HF. We hypothesized therefore that mTOR and its downstream substrates are central in this process. For proving this, we therefore generated an inducible and cardiac-specific mouse model defective in mTOR (mTOR-cKO). We found that upon loss of mTOR, mice developed dilated heart phenotype that progressed rapidly to death. Markers of autophagy and apoptosis increased significantly; importantly, the tumor suppressor gene p53 significantly accumulated in the heart of mTOR KO mice; moreover, there was a remarkable myocardial accumulation of active 4E-BP1, a downstream member of the mTOR pathway which negatively controls mRNA translation in its dephosphorylated form and a major substrate of TORC-1, one of the two mTOR kinase multiprotein complexes. We found that acumulation of dephosphorylated 4E-BP1 is a feature of HF of diverse etiologies, and thus might represent a common mechanism underlying this state. We also found that deleting 4E-BP1 in mice determines a very significant improvement of cardiac function and survival in the context of cardiac mTOR KO. In other cellular systems, 4E-BPs were shown to regulate p53 protein levels. The specific aims of this project therefore are 1) to determine the relative role of apoptosis and autophagy in mTOR-defective HF and in particular the role of the key gene p53 and 2) determine the role of 4E-BPs in mTOR-dependent HF as well as the reciprocal control between 4E-BPs and p53. These tasks will be accomplished through cross-breeding experiments of mTOR-cKO mice with strains in which Atg5, a gene critical for autophagy, or Nix, a gene critical for apoptosis, are deleted. Also, the role of p53 will be assessed by crossing our model with mice with p53-floxed alleles. Gene expression and proteomic studies will be conducted with the aim to identify genes critical for mTOR-cKO HF. The involvement of 4E-BPs in regulating cardiac function as well as p53 levels will be addressed by crossing mTOR-cKO with double 4E-BP1/4E-BP2 KO mice and by studying the role of p53 in regulating 4E-BP1 expression. Results of our research will assess the relative and reciprocal role of mTOR/4E-BP1 and p53 in controlling cardiac function in the normal and diseased heart, opening the possibility to interfere with these molecules for therapeutic purposes.
4 schema:endDate 2015-11-30T00:00:00Z
5 schema:funder https://www.grid.ac/institutes/grid.279885.9
6 schema:identifier N580ffe78997c4f1396a6af5f04ab1227
7 N988e8abbc3d0429d9543d5e039130d17
8 schema:inLanguage en
9 schema:keywords 4E-BP
10 4E-BP1
11 4E-BP1 expression
12 4E-BP1/4E
13 4E-BPs
14 Akt pathway
15 Atg5
16 BP2 KO mice
17 Myocardial mTOR activity
18 Nix
19 Regulating Cardiac Function
20 TORC-1
21 acumulation
22 aim
23 alleles
24 apoptosis
25 autophagy
26 cardiac function
27 cardiac mTOR KO
28 cardiac-specific mouse model
29 common mechanism
30 components
31 conditions
32 context
33 cross
34 death
35 decompensation
36 dephosphorylated forms
37 dilated heart phenotype
38 diseased heart
39 diverse etiologies
40 downstream members
41 downstream substrates
42 early phase
43 experiments
44 features
45 frank HF
46 gene expression
47 genes
48 heart
49 heart failure
50 hypertrophy switches
51 involvement
52 key gene p53
53 loss
54 mRNA translation
55 mTOR
56 mTOR KO mice
57 mTOR kinase multiprotein complexes
58 mTOR pathway
59 mTOR-cKO
60 mTOR-cKO HF
61 mTOR-cKO mice
62 mTOR-defective HF
63 mTOR-dependent HF
64 mTOR/4E-BP1
65 major substrate
66 mammalian target
67 markers
68 mice
69 model
70 molecules
71 other cellular systems
72 overall aim
73 p53
74 p53 levels
75 p53 protein levels
76 pathway
77 possibility
78 pressure overload hypertrophy
79 process
80 project
81 project summaries
82 proteomic studies
83 rapamycin
84 reciprocal control
85 reciprocal role
86 relationship
87 relative roles
88 remarkable myocardial accumulation
89 research
90 results
91 role
92 significant improvement
93 specific aim
94 state
95 strains
96 survival
97 task
98 therapeutic purposes
99 tumor suppressor gene p53
100 schema:name Role of mTOR, a Component of the Akt Pathway, in Regulating Cardiac Function
101 schema:recipient N62b2dae2a3224104b2bbd72f7abe4bae
102 sg:person.01321112106.55
103 https://www.grid.ac/institutes/grid.266100.3
104 schema:sameAs https://app.dimensions.ai/details/grant/grant.2540161
105 schema:sdDatePublished 2019-03-07T11:58
106 schema:sdLicense https://scigraph.springernature.com/explorer/license/
107 schema:sdPublisher N2037deacdc1e453b8dfb09aeb353d1a5
108 schema:startDate 2004-12-01T00:00:00Z
109 schema:url http://projectreporter.nih.gov/project_info_description.cfm?aid=8585080
110 sgo:license sg:explorer/license/
111 sgo:sdDataset grants
112 rdf:type schema:MonetaryGrant
113 N2037deacdc1e453b8dfb09aeb353d1a5 schema:name Springer Nature - SN SciGraph project
114 rdf:type schema:Organization
115 N580ffe78997c4f1396a6af5f04ab1227 schema:name dimensions_id
116 schema:value 2540161
117 rdf:type schema:PropertyValue
118 N62b2dae2a3224104b2bbd72f7abe4bae schema:member sg:person.01321112106.55
119 schema:roleName PI
120 rdf:type schema:Role
121 N988e8abbc3d0429d9543d5e039130d17 schema:name nih_id
122 schema:value R01HL078797
123 rdf:type schema:PropertyValue
124 Na9bba20b790f4ab5bd677cbc2d571ea1 schema:currency USD
125 schema:value 2975056
126 rdf:type schema:MonetaryAmount
127 anzsrc-for:2211 schema:inDefinedTermSet anzsrc-for:
128 rdf:type schema:DefinedTerm
129 sg:person.01321112106.55 schema:affiliation https://www.grid.ac/institutes/grid.266100.3
130 schema:familyName KNOWLTON
131 schema:givenName KIRK U
132 rdf:type schema:Person
133 https://www.grid.ac/institutes/grid.266100.3 schema:name UNIVERSITY OF CALIFORNIA SAN DIEGO
134 rdf:type schema:Organization
135 https://www.grid.ac/institutes/grid.279885.9 schema:Organization
 




Preview window. Press ESC to close (or click here)


...