# TR&D3: Metabolic Programming

> **NIH NIH P41** · JOHNS HOPKINS UNIVERSITY · 2020 · $322,208

## Abstract

The ultimate goal of immune-engineering is to harness the exquisite specificity of the immune
system to prevent and treat disease. However, it is becoming increasingly clear that cellular metabolic
programming is not merely a consequence of immune cell activation but rather an integral component of
promoting differentiation and function. The generation of cells with robust effector function is intimately
dependent upon the generation of nucleic acid, lipid and protein substrates, and energy. Likewise, persistence
or the induction of immunologic “memory” is dependent upon metabolic reprogramming that fuels long term
survival. In this context successful engineering of immune cells will entail modulation, programming and even
reprogramming of energy and substrate-generating metabolic programs. Initially based on our studies
dissecting the role of the mTOR pathway in regulating immune responses our lab has defined specific
nodes/targets to regulate metabolic programming necessary to fuel effector function and long term persistence.
TR&D 3 seeks to exploit these findings to target these critical nodes in order to engineer metabolic
reprogramming of cells, thus maximizing function and persistence. To this end we will pursue the following
Aims: Aim 1. Employing synthetic biology, genetically egineer cells with enhanced mTORC1 activity by
knocking down/out/mutating TSC2, leading to enhanced effector function characterized by more robust
glycolytic reprogramming. Deliverable: The creation of a reprogrammed “stock” effector cell that can then be
modified for an array of cellular therapies. Aim 2. By regulating glutamine metabolism, formulate growth and
differentiation conditions that promote the generation of cells epigenetically programmed to persist when
adoptively transferred in vivo and to maximally respond upon rechallenge. Deliverable: Metabolically
optimized media for producing robust and persistent effector cells. Aim 3. Based on novel findings regarding
the ability of SGK1 to promote both a memory and effector T cell phenotype, develop small molecule inhibitors
of SGK1 that can metabolically reprogram T cells both ex vivo and in vivo. Deliverable: Small molecule
inhibitors to enhance efficacy of Adoptive Cellular Therapy.

## Key facts

- **NIH application ID:** 10018000
- **Project number:** 5P41EB028239-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** JONATHAN D POWELL
- **Activity code:** P41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,208
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018000

## Citation

> US National Institutes of Health, RePORTER application 10018000, TR&D3: Metabolic Programming (5P41EB028239-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10018000. Licensed CC0.

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