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Fraz Ahmed Ismat, MDClinical Associate in Pediatrics, Division of Cardiology
The Children’s Hospital of Philadelphia
The Ras-t of the story…
Intracellular signaling incardiovascular development & disease
Nf1-/- embryos die of cardiovascular failure
Jacks T. et al., Nat Gen 1994
Nf1-/- hearts have a lethal series of defects
wild typee13.5
Nf1 -/-
e13.5
Gitler, et al., Nat Gen 2003
GRD expression rescues Nf1-/- embryonic heart defects
NF1 GRD expression rescues pericardial effusion ( ), enlarged endocardial cushion (arrows), and myocardial thinning (arrowheads).
*
Ismat et al., JCI 2006
GRD expression rescues Nf1-/- embryonic lethality
Nf1+/+ 13 17 27
Nf1+/+, GRDk/+ 13 17 13
Nf1+/+, CMV-cre+ 13 17 15
Nf1+/+, GRDk/+, CMV-cre+ 13 17 17
Nf1+/- 26 35 22
Nf1+/-, GRDk/+ 26 35 40
Nf1+/-, CMV-cre+ 26 35 37
Nf1+/-, GRDk/+, CMV-cre+ 26 35 32
Nf1-/- 13 0 0
Nf1-/-, GRDk/+ 13 0 0
Nf1-/-, CMV-cre+ 13 0 0
Nf1-/-, GRDk/+, CMV-cre+ 13 0 5*
Genotype Mendelian Expected Observed
Genotypes of 208 P0 pups from Nf1 +/-, GRD k/+ × Nf1 +/-, CMV-cre +.
Ismat et al., JCI 2006
Generation of Nf1 myocardial “knock-out” (Nf1mKO)
Late mortality in Nf1mKO
n=23
n=20
Progressive cardiac hypertrophy & fibrosis in Nf1mKO
Cardiac dilation & reduced shortening in Nf1mKO
Rescue of Nf1mKO cardiac hypertrophy with NF1 GRD
Marin, et al., JCI (in press)
LEOPARD syndrome mice have enlarged hearts
Wild type LS/+
Rapamycin rescues LS/+ cardiac hypertrophy
LS/+ LS/+ rapamycin
0.0054
0.0056
0.0058
0.006
0.0062
0.0064
0.0066
0.0068
0.007
0.0072
0.0074
WT LS LS + Rapa
**
HW
/BW
Rat
io
Marin, et al., JCI (in press)
Wild type
Acknowledgements
Past support: a Young Investigator Award from the Children’s Tumor Foundation, a Physician Scientist Development Award (K08) from the NHLBI;
Current support: a Basil O’Connor scholarship from the March of Dimes Foundation, a cardiovascular research grant from the W.W. Smith Charitable Trust,
and grants from the CHOP Cardiac Center Scientific Review Committee.
Ismat LabAlmedia McCoyTimothy Macatee
MCRC Core FacilitiesHistology Core (MM Lu)Transgenic Core (D Zhu)Physiology Core (T Wang*)
Penn Core FacilitiesFlow Cytometry & Cell SortingSmall Animal ImagingMicroarray Core Facility
Collaborators & Others
Jonathan Epstein (Penn)Aaron Gitler (Penn)Elizabeth Goldmuntz (CHOP)Tyler Jacks (MIT)Maria Kontaridis (BIDH-HMS)Thomas Look (DFCI)Arun Padmanabhan (Penn)Luis Parada (UTSW)Nancy Ratner (Cincinnati)Xin Zhang (IUPUI)Yuan Zhu (Michigan)