The purpose of this proposal is to better understand the role of cholesterol in normal embryonic development. The role of cholesterol has recently been highlighted by the discovery that mutations of the sterol delta-7 reductase (DHCR7), the last enzyme in the cholesterol biosynthesis pathway, cause the Smith-Lemli-Opitz Syndrome (SLOS, MIM 270400). SLOS is a relatively common multiple congenital abnormality syndrome, affecting embryonic development of brain, heart, limbs, intestine and lungs, as well as a number of other organs. Sterol delta-7 reductase is predicted to be a 9 transmembrane-domain spanning integral membrane protein localized to the endoplasmic reticulum and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. Understanding the biology of cholesterol metabolism during embryonic development is therefore of some importance. In addition, understanding the molecular biology of sterol delta-7 reductase, how the mutations disrupt this enzyme and gaining a better understanding of this enzyme may allow us, in the future, to devise better strategies to treat patients with Smith-Lemli-Opitz syndrome. To accomplish this, we have combined the powerful approaches of genetics, animal models, and cell biology to elucidate structure-function and biological relationships. We have developed a mouse model for SLOS, using targeted disruption of the murine dhcr7 gene. We will use tissue-specific in vivo complementation to abrogate the neonatal lethality of the homozygous knock out mice. Additionally, molecular characterization of both the knockout mice, as well as our in vitro studies will help us better understand the mechanistic processes involved in both the pathogenesis of SLOS, as well as the normal role of cholesterol in embryogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068660-02
Application #
6619483
Study Section
Metabolism Study Section (MET)
Program Officer
Ershow, Abby
Project Start
2002-08-01
Project End
2006-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$354,810
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Tint, G S; Pan, Luxing; Shang, Quan et al. (2014) Desmosterol in brain is elevated because DHCR24 needs REST for Robust Expression but REST is poorly expressed. Dev Neurosci 36:132-42
Matabosch, Xavier; Rahman, Mahbuba; Hughes, Beverly et al. (2009) Steroid production and excretion by the pregnant mouse, particularly in relation to pregnancies with fetuses deficient in Delta7-sterol reductase (Dhcr7), the enzyme associated with Smith-Lemli-Opitz syndrome. J Steroid Biochem Mol Biol 116:61-70
Yu, Hongwei; Wakim, Bassam; Li, Man et al. (2007) Quantifying raft proteins in neonatal mouse brain by 'tube-gel'protein digestion label-free shotgun proteomics. Proteome Sci 5:17
Solca, Curzio; Pandit, Bhaswati; Yu, Hongwei et al. (2007) Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse. Mol Genet Metab 91:7-14
Yu, Hongwei; Li, Man; Tint, G Stephen et al. (2007) Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice. BMC Dev Biol 7:27
Tint, G S; Yu, Hongwei; Shang, Quan et al. (2006) The use of the Dhcr7 knockout mouse to accurately determine the origin of fetal sterols. J Lipid Res 47:1535-41
Yu, H; Patel, S B (2005) Recent insights into the Smith-Lemli-Opitz syndrome. Clin Genet 68:383-91
Yu, Hongwei; Wessels, Andy; Tint, G Stephen et al. (2005) Partial rescue of neonatal lethality of Dhcr7 null mice by a nestin promoter-driven DHCR7 transgene expression. Brain Res Dev Brain Res 156:46-60
Yu, Hongwei; Wessels, Andy; Chen, Jianliang et al. (2004) Late gestational lung hypoplasia in a mouse model of the Smith-Lemli-Opitz syndrome. BMC Dev Biol 4:1
Klett, Eric L; Patel, Shailesh (2003) Genetic defenses against noncholesterol sterols. Curr Opin Lipidol 14:341-5

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