Transcriptional activation for rare disease rescue - ABSTRACT
Phosphoinositides (PI) are a highly regulated class of lipids in cell signaling and metabolism. Enzymatic
deficiency of PI kinases and phosphatases are known to result in severe multisystemic diseases such as Lowe
syndrome. A devastating X-linked recessive disease, Lowe syndrome can cause severe developmental delays,
cataracts, glaucoma, and renal failure that results in early demise. Mutations in OCRL, an inositol 5-phosphatase,
are found to be causal for Lowe syndrome. OCRL hydrolyzes PI(4,5,)P2 and PI(3,4,5)P3 into PI4P and PI(3,4)P2,
respectively, and it has been implicated in several cellular functions including endocytosis, ciliogenesis, and actin
cytoskeleton remodeling, which is likely to reflect the role that the phosphoinositides play in these processes.
OCRL has a paralog 5-phosphatase INPP5B, which may be able to compensate for the loss of OCRL by
regulating inositol metabolism. OCRL and INPP5B share the same substrates, the same domains, and are
known to interact with some of the same effector proteins. In addition, several groups, including ours, have
observed that overexpression of INPP5B can rescue Lowe fibroblast defects. Since we have also observed that
regulating the subcellular localization of the 5-phosphatase domain of OCRL can mediate defects observed in
Lowe patient cells, my hypothesis is that stimulation of INPP5B expression will compensate, at least partially, for
loss of OCRL in Lowe syndrome, and therefore offers a targeted therapy for Lowe syndrome. I will test this
hypothesis by 1) repurposing FDA-approved molecules to increase INPP5B levels and 2) by using optogenetics
to control the subcellular localization of the INPP5B 5-phosphatase domain. We will measure the functional
rescue by analyzing actin cytoskeletal arrangement and PI(4,5)P2 accumulation in Lowe patient cells and by
measuring the effect on glaucoma through regulation of intraocular pressure in Lowe syndrome mice. The
research proposed here will be used as a foundation to develop my own research program investigating how
defects in inositol metabolism and the primary cilia play a role in disease and to identify novel treatments for
these diseases.
