This application for RO3 award is submitted in response to PAR-01-066, """""""" Small grant program for KO8 recipients"""""""" and is linked to NIH KO8 DK02825-03. With the support of the KO8 funding, the applicant has completed his post-doctoral research training and has begun an independent research career. This grant will increase fiscal independence and provide an opportunity to generate data in a relatively new area of research for the applicant that can form the basis for an RO1 application. Preeclampsia (PE) is a disease characterized by severe hypertension, proteinuria and edema and occurs in 5% of all pregnancies. Endothelial dysfunction plays an important role in the pathogenesis of this disorder; however the etiology and mechanisms are still unknown. There is accumulating evidence for a pathogenic model for PE whereby a hypoxic feto-placental unit secretes a factor into the maternal circulation causing generalized endothelial cell dysfunction. In the first half of the proposal the applicant wishes to identify de novo targets in PE using mRNA expression profiling in normal and preeclamptic placentas. The applicant wishes to use bioinformatic tools such as hierarchical clustering and k-means to identify clusters of genes that will predict the occurrence and severity of PE. These studies will lead to identification of biomarkers, which may be used diagnostically and potentially lead to new therapies for this complex disorder. In preliminary experiments using gene expression profile from preeclamptic placentas, the applicant has identified """"""""sflt-1"""""""" (soluble fms-like tyrosine kinase) as a factor that is up-regulated in patients with PE. Flt-1 is one of the tyrosine kinase receptors for vascular endothelial growth factor (VEGF) and placental growth factor (PGF). Sflt-1, a secreted splice variant of fit-1 (lacking the transmembrane and cytoplasmic domains) is a potent antagonist of VEGF and PGF, by preventing both VEGF and PGF from interacting with its cell-surface receptor. The second half of the proposal will be to define the role of sflt-1 in the pathogenesis of PE. We will test the hypothesis that sflt-1, which is released by preeclamptic placenta, is responsible for some or all of the in vitro and in vivo phenotypes associated with PE. These focused studies form the beginnings of a framework to understand the pathogenesis of PE. The applicant has just begun his career as an independent investigator in July 2001. The applicant is highly motivated and absolutely committed to a career as a physician-scientist. The experience of the applicant in endothelial cell biology, the expertise of various collaborators and the supportive environment at Harvard Medical School provides an ideal forum for the applicant to not only realize the objectives of this proposal but also to become a successful independent investigator.
| Levine, Richard J; Qian, Cong; Maynard, Sharon E et al. (2006) Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women. Am J Obstet Gynecol 194:1034-41 |
| Karumanchi, S Ananth; Stillman, Isaac E (2006) In vivo rat model of preeclampsia. Methods Mol Med 122:393-9 |
| Venkatesha, Shivalingappa; Toporsian, Mourad; Lam, Chun et al. (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12:642-9 |
| Maynard, Sharon E; Venkatesha, Shivalingappa; Thadhani, Ravi et al. (2005) Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia. Pediatr Res 57:1R-7R |
| Lam, Chun; Lim, Kee-Hak; Kang, Duk-Hee et al. (2005) Uric acid and preeclampsia. Semin Nephrol 25:56-60 |
| Levine, Richard J; Karumanchi, S Ananth (2005) Circulating angiogenic factors in preeclampsia. Clin Obstet Gynecol 48:372-86 |
| Karumanchi, S Ananth; Maynard, Sharon E; Stillman, Isaac E et al. (2005) Preeclampsia: a renal perspective. Kidney Int 67:2101-13 |
| Thadhani, Ravi; Mutter, Walter P; Wolf, Myles et al. (2004) First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab 89:770-5 |
| Wolf, Myles; Hubel, Carl A; Lam, Chun et al. (2004) Preeclampsia and future cardiovascular disease: potential role of altered angiogenesis and insulin resistance. J Clin Endocrinol Metab 89:6239-43 |
| Thadhani, Ravi; Ecker, Jeffrey L; Mutter, Walter P et al. (2004) Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia. Hypertension 43:988-92 |
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