Identifying Thrombosis Modifier Genes in the Mouse The genetic factors responsible for the highly variable clinical course of patients with factor V Leiden and other forms of thrombophilia are unknown.
Aim 1 of this project will identify a large subset of potential thrombosis modifier genes within the mammalian genome using a whole genome ENU mutagenesis strategy in the mouse. We previously reported a uniformly lethal, perinatal thrombosis in mice homozygous for the factor V Leiden mutation (FvQ/Q) and heterozygous for Tfpi (Tfpi+/-). In preliminary studies, we used this phenotype as the basis for a large scale genetic suppressor screen. Mutagenized FvQ/Q males were bred with doubly heterozygote (FvQ/+Tfpi+/-) females and >6300 surviving G1 offspring genotyped to identify rare FvQ/QTfpi+/- animals who have survived the otherwise uniform perinatal lethality, presumably due to the suppressing effect of a mutated (haploinsufficient) modifier gene. As proof of principal, a genetic cross with TF knockout mice demonstrates that mutation at the TF locus will rescue the lethal FvQ/Q Tfpi+/- genotype. To date, 82 candidate suppressor mutants have been identified. Though most of these mutants have been lost due to decreased survival and/or infertility, genetic mapping for 7 of these lines is in progress and an additional 4 lines are undergoing progeny testing. We will expand this screen to achieve 4-6 fold genome coverage and identify the corresponding genes by positional cloning.
Aim 2 will further characterize a strain specific modifier of the FvQ/QTfpi+/- lethal phenotype identified in the DBA/2J strain, by a similar positional cloning strategy.
Aim 3 will take advantage of natural strain variation in the mouse to identify genetic factors critical for susceptibility to thrombotic thrombocytopenic purpura (TTP). Previous work by us and others suggests that deficiency of the metalloprotease ADAMTS13 is necessary, but not sufficient for the development of TTP in humans and in mice. In preliminary studies, we have shown that the development of TTP in ADAMTS13 null mice is dependent on genetic factors differing among mouse strains. Genetic crosses between susceptible and resistant strains will be performed to identify the underlying gene(s), which should provide critical insight into the pathogenesis of TTP as well as offering candidates for useful diagnostic and prognostic markers in humans. Relevance: These studies should provide new insight into the regulation of blood clotting, and identify a number of genes that may be important predictors of severity for many common inherited blood clotting diseases. This information may also suggest new approaches to therapy for these conditions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Michigan Ann Arbor
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Ji, Yan; Weng, Zhen; Fish, Philip et al. (2016) Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation. Arterioscler Thromb Vasc Biol 36:2167-2175
Khoriaty, Rami; Everett, Lesley; Chase, Jennifer et al. (2016) Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice. Sci Rep 6:27802
Xu, Xianjin; Ma, Zhiwei; Sun, Hongmin et al. (2016) SM-TF: A structural database of small molecule-transcription factor complexes. J Comput Chem 37:1559-64
Emmer, Brian T; Ginsburg, David; Desch, Karl C (2016) Von Willebrand Factor and ADAMTS13: Too Much or Too Little of a Good Thing? Arterioscler Thromb Vasc Biol 36:2281-2282
Khoobchandani, Menka; Katti, Kavita; Maxwell, Adam et al. (2016) Laminin Receptor-Avid Nanotherapeutic EGCg-AuNPs as a Potential Alternative Therapeutic Approach to Prevent Restenosis. Int J Mol Sci 17:316
Tomberg, Kärt; Khoriaty, Rami; Westrick, Randal J et al. (2016) Spontaneous 8bp Deletion in Nbeal2 Recapitulates the Gray Platelet Syndrome in Mice. PLoS One 11:e0150852
Fribley, Andrew M; Miller, Justin R; Brownell, Amy L et al. (2015) Celastrol induces unfolded protein response-dependent cell death in head and neck cancer. Exp Cell Res 330:412-22
Wu, Jianbo; Strawn, Tammy L; Luo, Mao et al. (2015) Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-αVβ3 integrin cross talk. Arterioscler Thromb Vasc Biol 35:111-20
Sun, Hongmin (2015) Factor V: an active player in inflammation. Blood 126:2352-3
Kretz, Colin A; Dai, Manhong; Soylemez, Onuralp et al. (2015) Massively parallel enzyme kinetics reveals the substrate recognition landscape of the metalloprotease ADAMTS13. Proc Natl Acad Sci U S A 112:9328-33

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