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Einstein-Hevolution Partnership
To understand the mechanisms that govern the initiation, maintenance and resolution of senescence in order to determine how these pathways are modulated by the hallmarks of aging and to use these insights to develop novel, clinically-ready, rational-based senotherapeutics
PROJECT 1
Senescence and Cell Death can be triggered by cellular stress and damage. We seek to:
Understand the fundamental mechanisms and pathways that determine which fate an uncommitted cell ultimately pursues following age-related stress or damage.
Delineate how this cell fate decision is influenced by chronological aging and drivers (hallmarks) of aging.
Leverage this information to guide therapeutic development
PROJECT 2
Senescent cells in old organisms may persist due to a combination of cell-autonomous changes within the senescent cell and a functional decline of the immune system with age. Here we seek to:
Understand molecular adaptations required to maintain a stable senescent state thereby uncovering unique vulnerabilities that can be exploited for therapeutic purposes
Identify how biological age and activation of specific aging hallmarks affect senescence maintenance
Identify molecular pathways activated within the senescent cell or in the immune system that are essential for senescence resolution and immune clearance
Determine how molecular pathways required for senescent cell clearance change with age
PROJECT 3
The goal of this project is to establish novel targeted therapeutic strategies and lead molecules that target unique vulnerabilities of the cellular senescence state and efficiently remove senescent cells. This project will focus on: 1) small molecule drug discovery and medicinal chemistry capabilities for the novel targets provided by Projects 1 and 2 to advance small molecules to lead stage and successful in vivo proof of concept studies for at least two different targets; 2) further lead optimization studies for one small molecule project to advance to a developmental candidate stage (pre-IND enabling studies). We will:
Facilitate target identification and perform target druggability assessment, assay development, in silico screening, hit selection and validation using state-of-art chemical biology technologies
Provide chemical synthesis and medicinal chemistry capabilities to generate novel senolytics with drug-like properties.
Optimize compounds for pharmacological efficacy and safety using an iterative process of medicinal chemistry
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