The Blind Lab

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My research attempts to understand how biological systems store, transfer and use non-genomically encoded information. We do this by studying the structure and function of lipids in the nucleus of mammalian cells. We study nuclear lipids because these molecules have particular qualities that allow us to discover new ways genes can be turned on and off, how genetic messages are encoded, and how information is transferred between cellular compartments.  All this work helps us identify pathological signaling in human diseases, giving us a way to chemically interfere with those pathologies to help develop new therapeutics. 

Now, allow me to tell you a little about my scientific history!

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College:  With David Koetje at Fredonia State I studied how plants communicate with each other using an atmospheric chemical released in response to leaf damage called methyl jasmonate. Leaf damage is an indication of herbivore attack, and we discovered that treatment of tobacco plants with atmospheric methyl jasmonate induced dramatic changes in gene expression. The highly volatile jasmonate produced by plants under attack caused photosynthetic genes to be shut down in favor of genes that produce defensive, indigestible molecules in plants not under attack, but which are closeby. This action communicates the attack between plants, dissuading herbivore browsing in nearby plants.

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Grad School:  With Michael Garabedian at NYU I studied how information can be stored within a "phosphorylation code" of the glucocorticoid nuclear receptor (GR). We showed that certain phosphorylated species of GR were recruited more to genes than others, and that specific phospho-isoform recruitment correlated with how well that gene was turned on. 

Postdoc:  With Holly Ingraham and Robert Fletterick at UC San Francisco, I studied how information is encoded into the phospholipid headgroups of nuclear lipids. This type of encoding was well known to occur in cytoplasmic membranes, authored by a group of enzymes called "lipid signaling enzymes". However, it was unknown if those same enzymes worked the same way in the nucleus, because the bulk of phospholipids in the nucleus exist outside membranes, tightly bound to nuclear proteins in every eukaryotic organism ever examined, from yeast to plants to humans. Despite this high conservation and penetrance, almost nothing was known about nuclear lipid structure, function, the activity of signaling enzymes on nuclear lipids, or the identity of the nuclear phospholipid receptors.

I identified the only known nuclear receptor for phosphoinositides called "SF-1". Using many biophysical approaches, I showed that the physicochemical format of phosphoinositides bound to SF-1 enhances the lipid phosphatase activity of PTEN, as well as the PI3-kinase activity of a poorly studied inositol lipid kinase called “Inositol Polyphosphate Multikinase” (IPMK). PTEN & IPMK achieve better catalysis since the nuclear receptor “presents” the lipid headgroup to PTEN and IPMK. In contrast, the classic p110 PI3-kinases unable to act on PIP2 bound to this SF-1 nuclear receptor. Despite the exciting potential to make new inroads in understanding PTEN-negative cancers and IPMK action in the diabetic liver, the IPMK & PTEN enzyme activities described above have never been explored in any model of cancer or diabetes. Today, postdocs and students in the lab are following up on this work.

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Investigator:  If you've read this far, allow me to tell you about a more obscure project I am currently very interested in. The problem is very fundamental: how can branches of highly interconnected signaling networks be decoupled from one another, allowing activation of specific circuits within highly integrated signaling architectures?  Although signaling dynamics and spatiotemporal mechanisms clearly can achieve this goal, it remains unclear if these are the only ways cells can achieve specificity within integrated networks. SF-1 is an excellent model to address this question, as it forms dynamic complexes with several distinct lipid species (phosphatidylinositols, phosphatidylcholines and sphingolipids). This property is important since lipids bound to SF-1 are modified by IPMK & PTEN, regulating SF-1 biological activity. Thus, a particular SF-1/lipid complex can interface with a lipid signaling enzyme only if SF-1 has been loaded with a chemically compatible lipid substrate. This new mechanism permits dynamic downstream responsiveness to constant upstream input, disentangling specific pathways from the full cellular signaling network. 

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Thus, I want to use nuclear lipid signaling to discover novel ways biological systems store, transfer and use information, and then apply those discoveries to the treatment of human pathologies such as cancer and diabetes. I am trying to make this happen by developing novel classes of therapeutics that act as signaling shunts, directing a diseased system into a therapeutically favorable state by modulating how those systems store, transfer and use information through the basic mechanisms we uncover in the lab. This approach is far more subtle than classic drug development by pharmaceutical companies, with potential to impact patients who are still waiting for therapies that can help them.

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