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Decoding the Assembly and Function of Paralogue Specific SIN3A and SIN3B Human Chromatin Remodeling Complexes and Networks

Award Number: R35GM145240
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Decoding the Assembly and Function of Paralogue Specific SIN3A and SIN3B Human Chromatin Remodeling Complexes and Networks - ABSTRACT Paralog switching in chromatin remodeling complexes plays a key role in development and loss of regulatory control over chromatin paralog functions is closely linked to many types of cancer. Human SIN3A and SIN3B are amongst this class of important chromatin remodeling paralogs. SIN3A mutations are considered driver mutations in uterine corpus endometrial carcinoma, and both SIN3A and SIN3B haploinsufficiency linked to human neurodevelopmental disorders. Human SIN3A and SIN3B are members of several large multiprotein complexes involved in chromatin remodeling containing the histone deacetylase enzymes HDAC1 and HDAC2. While the overall members of the SIN3A and SIN3B complexes is largely known, the structure and function of specific complexes in these networks remain poorly understood. Furthermore, the precise targeting of gene repression by SIN3/HDAC-mediated histone deacetylation is likely controlled by the non-catalytic SIN3 subunits but also remains enigmatic. These fundamental gaps in knowledge regarding the structure and function of SIN3A and SIN3B containing complexes limit our ability to devise specific therapeutic interventions in cancer, for example. The overarching goal of the research in the laboratory is to understand the molecular mechanisms of how specific SIN3A and SIN3B complexes regulate gene expression and chromatin remodeling in normal and diseased human conditions. We are in a unique position to advance the understanding of these area of research based on my strong track record and long-standing expertise in chromatin remodeling and proteomics, assembled team of collaborators, and multidisciplinary approach. In our lab, we continually develop new proteomic technologies and apply them to chromatin remodeling complexes and networks. Here, we will use a comprehensive approach of affinity purification, enzyme kinetics, peptide synthesis, fluorescence microscopy, genomics, quantitative proteomics, cross linking mass spectrometry, and integrative structural modeling. Using these methodologies over the next five years, we will investigate 1) How are SIN3A and SIN3B complexes assembled, 2) What are the regulatory functions of specific subunits, 3) How do SIN3A complexes regulate specific transcription factor function, 4) What are the SIN3A and SIN3B networks in endometrial cells, and 5) How can we disrupt protein protein interactions in these complexes? This set of questions will go from a fundamental structure and function of these complexes to determining the role of specific complexes in important human cellular models. We will lay the foundation to address the gap in knowledge in the diversity and function of specific chromatin remodeling complexes. In addition, we will begin to develop new therapeutic strategies to target specific chromatin remodeling complexes. With this information in hand, we will be closer to our long-term goal and vision of designing peptide-based approaches to disrupt specific protein complexes as novel and specific cancer therapeutic agents.


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 = $387,500 )
2026	2026	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	000	5	5/19/2026	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2025 ( Subtotal = $387,500 )
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	001	4	5/6/2025	NON-COMPETING CONTINUATION	$387,500
2025	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	000	3	12/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,500

Issue Date FY: 2024 ( Subtotal = $387,500 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	000	3	5/10/2024	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2023 ( Subtotal = $387,500 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	000	2	5/23/2023	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2022 ( Subtotal = $387,500 )
2022	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Biomedical Research and Research Training	000	1	8/8/2022	NEW	$387,500
														Subtotal = $387,500

Grand Total All Awards = $1,937,500

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Decoding the Assembly and Function of Paralogue Specific SIN3A and SIN3B Human Chromatin Remodeling Complexes and Networks

Award Number: R35GM145240

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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