Leucyl tRNA Synthetase Screening for mTORC1 Disease
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Solution Overview
Problem
Current methods fail to effectively address the activation of the mTORC1 pathway and the regulation of cell growth, particularly in response to amino acid availability, due to the unknown mechanisms of intracellular leucine sensing and GTP/GDP cycles of Rag GTPases.
Innovation Solution
Leucyl tRNA synthetase (LRS) is identified as an mTORC1-associated protein that directly interacts with Rag GTPase, functioning as a GTPase-activating protein to activate mTORC1, and a method is developed to screen agents that inhibit this interaction to prevent or treat mTORC1-mediated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If LRS is used to activate mTORC1 pathway for cell growth regulation, then protein synthesis and cell metabolism are improved, but risk of mTORC1-mediated diseases (cancer, autoimmune diseases, diabetes, obesity, cardiovascular diseases) increases
Solution Approach 1:
The patent uses LRS as an intermediary molecule that can be targeted by screening agents. By identifying compounds that modulate LRS-RagD interaction, the patent provides a way to control mTORC1 activation indirectly, allowing therapeutic intervention without completely blocking the pathway, thus maintaining protein synthesis while preventing disease-associated overactivation
Solution Approach 2:
The patent employs screening methods to identify agents that change the binding affinity parameters between LRS and RagD. By modulating this interaction parameter, the pathway activation can be fine-tuned to achieve therapeutic effects - reducing overactivation in disease states while preserving necessary physiological function
2Reliability
If screening method targets LRS-RagD interaction to inhibit mTORC1 pathway, then disease treatment efficacy is improved, but understanding of intracellular leucine sensing mechanism remains incomplete
Solution Approach 1:
The patent establishes a screening platform based on LRS-RagD interaction before fully elucidating the complete leucine sensing mechanism. This preliminary approach allows therapeutic agent identification while research into the broader sensing mechanism continues, separating the immediate therapeutic need from complete mechanistic understanding
Solution Approach 2:
The patent extracts the LRS-RagD interaction as a specific targetable component from the broader leucine sensing system. By focusing on this discrete molecular interaction, the patent enables drug screening and development without requiring complete knowledge of all sensing mechanisms, isolating a therapeutically relevant subset of the pathway
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method allows for the identification of agents that modulate the binding affinity between LRS and RagD, providing a therapeutic approach for diseases such as cancer, autoimmune diseases, diabetes, obesity, and cardiovascular diseases by targeting the mTORC1 pathway.
Implementation Method 1
LRS directly interacts with Rag GTPase, functioning as a GTPase-activating protein to activate mTORC1
Data Source
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Figure 1e~1f
AI summary
The present invention relates to novel use of leucyl tRNA synthetase and more particularly it relates a method of screening an agent for preventing or treating mTORCl mediated diseases by screening an test agent which inhibits binding ability of LRS to RagD or RagD GTPases and a method of reducing cell size compared to the control group comprising inhibiting expression of intracellular LRS. The method of the present invention provides novel method of regulating cell size and further the screening method of screening can be used in developing novel reagent for treatment of disease such as cancer.