Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Engineer A Chemogenetic Toolbox for Unraveling Complex Signaling Networks

Award Number: R21EB036678
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/02/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2027

Group Awards By:

View Award Description

Engineer A Chemogenetic Toolbox for Unraveling Complex Signaling Networks - PROJECT SUMMARY Cancer remains a global health challenge despite significant advancements in diagnosis and treatment. In the past two decades, immunotherapy has dramatically changed the landscape of cancer treatment, with immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4/B7-1 showing notable success. However, these therapies benefit only a subset of patients, underscoring the need to explore additional immune regulatory mechanisms. The T cell immunoglobulin and ITIM domain (TIGIT) has been identified as another promising checkpoint for immunotherapy, with preclinical studies showing potential. However, clinical trials have revealed that anti-TIGIT monotherapy offers limited benefits for patients with advanced solid tumors. The intricate network of TIGIT signaling, characterized by its extensive crosstalk and interaction with other co-inhibitory and co- stimulatory pathways, suggests that targeting TIGIT alongside other pathways using bi- or trispecific antibodies might enhance antitumor efficacy. The primary challenge in leveraging this approach is target determination due to the complexity of TIGIT network, which is influenced by a delicate balance of various components, each contributing differently to immune regulation. Developing a quantitative model that accurately reflects the role of each element within the TIGIT pathways as well as their collective impact is crucial for devising effective targeted therapy combinations. However, the field faces substantial technical hurdles, especially in achieving precise, noninvasive, and simultaneous control of multiple protein components in T cells to assess their collective impact on immune suppression. To address this, we propose the development of a chemogenetic toolbox that allows for the controlled expression of multiple proteins. This toolbox will allow us to dissect the intricate immune suppression mediated by the diverse elements in the TIGIT network. This strategy utilizes destabilization domains (DDs) which, upon binding to specific small molecules (SMs), can modulate protein levels in a dose- dependent manner. Despite the availability of some DD:SM pairs, their application is limited by issues such as interference with endogenous systems, poor SM permeability, and lack of orthogonality. To address this and to study TIGIT signaling, our project is structured around three main objectives: (1) engineering new and orthogonal DD:SM pairs through molecular docking and advanced protein engineering to overcome existing limitations (Aim 1), (2) developing a high-throughput assay to unravel the complex immune inhibition orchestrated by various components within the TIGIT network and to establish a quantitative model (Aim 2), and (3) Generating bispecific antibodies that target critical elements within the TIGIT network to augment the immune response (Aim 3). Through this research, we aim to unlock new insights into TIGIT signaling and establish a solid framework for assessing the most effective therapeutic combinations, ultimately enhancing the arsenal of immunotherapy, and potentially improving outcomes for cancer patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $321,146 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	5/7/2026	NON-COMPETING CONTINUATION	$321,146
														Subtotal = $321,146

Issue Date FY: 2025 ( Subtotal = $321,146 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	7/2/2025	NEW	$321,146
														Subtotal = $321,146

Grand Total All Awards = $642,292

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Engineer A Chemogenetic Toolbox for Unraveling Complex Signaling Networks

Award Number: R21EB036678

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/02/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer