# Chemical and structural tools to study energy homeostasis pathways in cancer and diabetes

> **NIH NIH R35** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $423,479

## Abstract

Project Abstract
 The overall goal of the lab is to study the role of energy homeostasis pathways in human disease using
structural and chemical tools. Our lab focuses on two major fundamental pathways: O-GlcNAcylation and
autophagy. The first major focus on the lab is on glycosylation, which plays a fundamental role in living organisms
and is misregulated in several human diseases. A unique form of glycosylation in mammals involves the essential
enzyme O-GlcNAc transferase (OGT), which dynamically transfers a single sugar on to nuclear and cytoplasmic
proteins to modulate signaling, transcription, and protein degradation. This single enzyme is responsible for
glycosylating over a thousand substrates. Aberrant OGT activity is associated with human diseases such as
cancer, diabetes, obesity, and neurodegeneration. However, the biology of this modification is quite complex
because of the abundance of substrates for a single enzyme. This complexity has prevented an understanding
of which substrates are important for human diseases, how OGT recognizes them, and how metabolic changes
alter the physiology of cells through this enzyme. We seek to better understand the mechanism of this
fundamental enzyme through a combination of biochemistry, structural biology, and chemical biology. Our major
goal is to clarify the complex role that nuclear and cytoplasmic protein glycosylation has in human disease.
 Autophagy is a conserved pathway that eukaryotic cells use to recycle materials from proteins to whole
organelles for energy and quality control. It has recently been shown that cancer cells rely on autophagy to
satisfy their increased energy demands and to resist chemotherapy. To study autophagy, our major goals are
developing new chemical inhibitors of a key enzyme that initiates autophagy called ULK1. Our other goal is to
find novel synthetic lethal interactors with autophagy by discovering other drugs that synergistically target cells
when autophagy is inhibited. Our vision is to develop advance screening systems to better mimic tumors and
look for new combinations of treatment that rely on blocking autophagy.

## Key facts

- **NIH application ID:** 9984489
- **Project number:** 5R35GM124838-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Michael Block Lazarus
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,479
- **Award type:** 5
- **Project period:** 2017-09-18 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984489

## Citation

> US National Institutes of Health, RePORTER application 9984489, Chemical and structural tools to study energy homeostasis pathways in cancer and diabetes (5R35GM124838-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9984489. Licensed CC0.

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