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AI-enhanced profiling of 3D-genome organization and transcriptional activity in the human brain

Award Number: F30AG101857
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/04/2027
PERIOD OF PERFORMANCE END DATE: 02/03/2028

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AI-enhanced profiling of 3D-genome organization and transcriptional activity in the human brain - Project Summary 3D-genome features such as chromatin organization and nuclear architecture are distinct indicators for biological processes such as cell differentiation, aging, and disease. The scale and complexity of the genome lead to significant technical challenges in the mapping of its spatial organization. To date, addressing these challenges has involved significant financial cost and experimental demands, which limit the application of 3D-genome technologies to disease and clinical applications. Additionally, existing spatially resolved 3D-genome methods have not yet been demonstrated in complex human tissue. In the human brain, the heterogeneity in tissue organization and cell types adds an additional layer of complexity to understanding the 3D-genome in neurological disease. Characterizing the 3D-genome human brain and neurological disease processes will improve our understanding of the molecular and cellular mechanisms of disease, and findings may enable diagnostic and therapeutic insights. Our proposed work will address these limitations by demonstrating the technology on human tissue and lowering costs. We will develop experimental and AI-enabled computational methods to extend joint RNA and DNA multiplexed error-robust fluorescent in situ hybridization (MERFISH) and apply it to the study of the human brain in both healthy and disease states. In Aim 1, we will extend DNA MERFISH and generate a spatially resolved single-cell map of 3D-genome organization in the human primary motor cortex. In Aim 2, we will integrate the above-developed map with existing AI methods to develop a framework for increasing scalability and reducing costs in 3D-genome studies, especially in the context of neurodegeneration and other neurological disease processes. In Aim 3, we will integrate DNA MERFISH with CRISPR-based perturbation screening and computational methods to mechanistically study 3D-genome changes in neurodegeneration and aging. Our proposed studies will provide fundamental insights into the chromatin organization and nuclear architecture of the human brain in healthy and disease states. More broadly, our work will pave the way for the application of advanced 3D-genome imaging technologies to the understanding, diagnosis, and treatment of human disease.


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 = $55,114 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	1	8/4/2026	NEW	$55,114
														Subtotal = $55,114

Grand Total All Awards = $55,114

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AI-enhanced profiling of 3D-genome organization and transcriptional activity in the human brain

Award Number: F30AG101857

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/04/2027

PERIOD OF PERFORMANCE END DATE: 02/03/2028

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