Our lab has shown that TGF-b is essential for normal angiogenesis (vascular development), and that it promotes tumor progression and tumor metastasis. Interestingly we have shown that the effect of reducing TGF-b signaling in vivo is highly variable between individuals, and that this is due to normal inter-individual genetic variation that occurs in both mouse and human populations. We are identifying and characterizing the variant genes that modify the effects of TGF-b signaling on vascular development and remodeling that occurs during embryogenesis and during malignant tumor progression. Characterization of these novel genes will provide new insight into the molecular mechanisms that regulate TGF-b biology in vivo, and may provide novel drug targets for disease treatment. This information may also allow us to predict disease risk, severity or prognosis, or to predict how individual patients might respond to TGF-b inhibitory drugs.  

This work is relevant to human vascular disease, since humans that have mutations in genes of the TGF-b pathway have vascular complications, such as Familial Pulmonary Arterial Hypertension (FPAH), Hereditary Hemorrhagic Telangiectasia (HHT), and Loeys-Dietz Syndrome (LDS). It is also important to cancer, since we know that in some tumor types, TGF-b signaling components are tumor suppressors but that in other tumor types TGF-b can promote malignant progression and metastasis, and that TGF- b1 effects are dependent on genetic context.

The approaches that we take involve generation and analysis of transgenic and gene knock-out mice that over-express or ablate TGF-b components. We also study the effects of innate genetic variation on the phenotypes of these transgenic and gene knock-out mice. We have found that the phenotypes can vary enormously depending on the presence of different variants of endogenous “modifier” genes within the genome. Again, this reflects the human condition, where genetic variants in other genes can alter the severity of phenotypes for FPAH, HHT and LDS. We have analyzed this innate genetic variation by undertaking large genetic crosses, and also by selective breeding of endogenous gene variants onto different mouse strain backgrounds to produce “congenic” mice. We then analyze these gain-of-function, loss-of-function and congenic animals for perturbations in embryonic development, tumor induction, tumor biology, as well as investigating effects on stem cells that give rise to both the vascular system and to tumors. Molecular and biological analysis of these mice, and cells derived from them, allows us to draw conclusions about the function of the modifier genes and how these contribute to vascular biology, cancer and other diseases. We also collaborate with clinicians and human geneticists to address how these syntenic genetic variants influence human disease.

What is the genetic makeup of these genetic modifier loci? Why do these loci influence so many diseases (cancer, vascular disease, inflammation, asthma)? What is the biological basis for the action of the modifiers - Action on tumor angiogenesis? Endothelial progenitor cells? Tumor stem cells? Immune system? What is the molecular basis for functional interaction between the TGF-b1 signaling pathway and the modifier genes?

Finally, we are administering to mice, novel drugs that are targeted against the TGF-b signaling components to investigate their utility as anti-cancer or anti-angiogenic agents in vivo. The findings have broad implications to major human diseases that include a vascular component and/or involve TGF-b, such a as cancer, athersclerosis and inflammation.