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Modeling Transcriptional Reprogramming by Markov Chain Monte Carlo Sampling

Award Number: R01LM011000
ORGANIZATION: NATIONAL LIBRARY OF MEDICINE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2012
PERIOD OF PERFORMANCE END DATE: 08/31/2015

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Modeling Transcriptional Reprogramming by Markov Chain Monte Carlo Sampling - DESCRIPTION (provided by applicant): Complex diseases, including cancer and multiple sclerosis, arise when multiple biological systems are impacted by molecular changes, such as gene mutation, gene silencing, or cellular modification by external agents. These molecular changes lead to changes in the cellular state, almost always including reprogramming of gene expression. Because biological systems are inherently complex and nonlinear, appropriate modeling of the system is required to recover knowledge of systems-level behavior in many cases. We focus in this proposal on methods to improve our ability to infer biological process activity from high- throughput data and on the development of biomarkers of these processes. We have developed a Markov chain Monte Carlo algorithm for analysis of microarray data that combines knowledge of transcriptional regulation and simple models of signaling networks to identify on-target and off- targets effects of therapeutics in cancer. Here we propose including prior knowledge in this algorithm by integrating data from pathways, gene mutations, methylation arrays, miRNA arrays, and protein-protein interactions (PPIs) to improve inference of cell behavior at a systems-level. Our first aim will develop an integrated model of signaling coupled to transcriptional reprogramming that couples knowledge of pathways to measurements of mutation status and miRNA levels to improve estimation of cell signaling. Our second aim will integrate methylation measurements and transcription factor binding site information as prior data to refine inference of targets of transcription factors to improve gene set inference and estimation of upstream signaling. Our third aim will develop a methodology to find reliable biomarkers from our models in light of multiple regulation of genes. Successful completion of the proposed work will provide novel open-source tools for improved inference on and biomarker identification of transcriptional reprogramming of cells. This will substantially improve inference of the specific changes that drive systems out of homeostasis and of treatment response in individual cases.


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: 2017 ( Subtotal = $0 )
2017	2014	COLLEGE OF NEW JERSEY, THE	2000 PENNINGTON RD	EWING	NJ	08628	MERCER	USA	Medical Library Assistance	000	3	12/9/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $286,343 )
2014	2014	COLLEGE OF NEW JERSEY (THE)	P.O. BOX 7718	EWING	NJ	08628	MERCER	USA	Medical Library Assistance	000	3	8/6/2014	NON-COMPETING CONTINUATION	$286,343
														Subtotal = $286,343

Issue Date FY: 2013 ( Subtotal = $271,584 )
2013	2013	COLLEGE OF NEW JERSEY (THE)	P.O. BOX 7718	EWING	NJ	08628	MERCER	USA	Medical Library Assistance	000	2	8/21/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$271,584
														Subtotal = $271,584

Issue Date FY: 2012 ( Subtotal = $328,000 )
2012	2012	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Medical Library Assistance	001	1	9/15/2012	NEW	$32,800
2012	2012	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Medical Library Assistance	000	1	8/30/2012	NEW	$295,200
														Subtotal = $328,000

Grand Total All Awards = $885,927

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Modeling Transcriptional Reprogramming by Markov Chain Monte Carlo Sampling

Award Number: R01LM011000

ORGANIZATION: NATIONAL LIBRARY OF MEDICINE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2012

PERIOD OF PERFORMANCE END DATE: 08/31/2015

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