# Directing Membrane Function with Inositol Lipids in Health and Disease

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $463,627

## Abstract

PROJECT SUMMARY/ABSTRACT
The plasma membrane (PM) is a bustling hub of transport, signaling and structural functions that sustain life at
the cellular level. Failure to appropriately choreograph these parallel functions contributes to the pathogenesis
of many diseases. Selective regulation of PM function relies on the cytosolic leaflet phosphoinositide (PPIn) lipid,
phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. PI(4,5)P2 is a master regulator, recruiting and/or activating
scores of proteins controlling PM permeability, vesicular traffic, cytoskeletal assembly and receptor-driven
signaling. Human diseases from cancer to rare monogenic disorders are known to be associated with aberrant
PI(4,5)P2 levels, which result from disrupted PI(4,5)P2 synthesis or breakdown. That said, the sheer number of
PI(4,5)P2-regulated functions has made it challenging to identify which functions contribute to disease
phenotype, let alone attempt therapeutic intervention. Therefore, the long-term goal of the lab's research is to
develop a detailed, mechanistic understanding of how PPIn metabolism couples to individual physiological
processes; ultimately, we aim to use this knowledge to develop strategies that modulate or restore PI(4,5)P2
regulation of individual functions that are aberrant in disease. Our goal in this application is to define three
distinct mechanisms by which metabolism of PM PI(4,5)P2 or its signaling products couple to multiple
physiological processes. In the first project, we leverage our recent discovery of a PM PI(4,5)P2 homeostatic
mechanism to experimentally tune the lipid level in cells: this will allow us for the first time to determine the
PI(4,5)P2 concentration-dependence of key PM functions. This will reveal which functions are most affected by
pathogenic PI(4,5)P2 levels and thus likely drive disease phenotypes – a crucial first step in devising therapeutic
interventions. In the second project, we will identify lipid transfer proteins (LTPs) that couple PPIn removal from
membranes to their degradation by PPIn phosphatases located in other organelles. We will employ a synthetic
biology approach in which LTPs deplete ectopic mitochondrial PPIn in live cells. Identifying LTPs coupled to
different PPIn pools will reveal new targets to prevent PPIn accumulation in monogenic disease where
phosphatase activity is lost. In the third project, we will define the distinct PI3K signaling landscapes driven by
the two downstream lipid products of PI(4,5)P2: PIP3 and PI(3,4)P2. We will define the unique spatiotemporal and
effector protein activation profiles of these lipids in live cells, using our unique molecular tools to precisely detect
and chemogenetically manipulate the lipids in cell culture. Crucially, this will identify spatiotemporal and effector
protein activation profiles that are unique to each lipid. This knowledge will be vital to eliminate on-target adverse
effects of proven PI3K therapeutics. Collectively, at the conclusion of thi...

## Key facts

- **NIH application ID:** 10739294
- **Project number:** 5R35GM119412-08
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Gerald R Hammond
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $463,627
- **Award type:** 5
- **Project period:** 2016-08-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10739294

## Citation

> US National Institutes of Health, RePORTER application 10739294, Directing Membrane Function with Inositol Lipids in Health and Disease (5R35GM119412-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10739294. Licensed CC0.

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