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Virus-driven human gene misregulation in disease

Award Number: R01AI205712
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Virus-driven human gene misregulation in disease - Thousands of genetic variants have been established for hundreds of human diseases. Likewise, environmental factors, including virus infection, play established, potent roles in disease. Yet, the vast majority of human diseases remain idiopathic. Functional genomics-based approaches from our group and others are revealing that changes in human chromatin state and gene expression are important molecular mechanisms through which genetic and environmental factors influence human disease risk. In particular, pioneering studies of the Epstein-Barr virus (EBV), which plays an established causative role in mononucleosis, Burkitt's lymphoma, Hodgkin lymphoma, and multiple sclerosis, have led to valuable insights into how virus-encoded transcriptional regulators (vTRs) interact with the human genome to modify human gene expression. More recently, functional genomic characterization of the impact of diverse viruses on human gene regulation by our group and others has revealed many additional impacted host mechanisms, many with disease-relevant consequences. Mounting evidence supports the hypothesis that risk allele-dependent binding of viral transcriptional regulators contributes substantially to virus-induced chronic diseases. However, the data required to systematically discover these mechanisms are currently far from complete. In this renewal, we propose a series of genome-scale experiments and computational methodologies aimed at the comprehensive discovery of virus- induced human gene regulatory mechanisms that lead to disease. In our previous round of funding, we built a strong foundation revealing the functional impact of introducing each individual vTR into human cells on a whole genome scale, for each of the seven major herpesvirus and four disease-relevant strains of human papilloma virus. Here, we build upon this foundation by examining these mechanisms in the context of full virus infection. Using these data, we will discover new allele- and virus-dependent mechanisms and build an unprecedented, freely available resource for studying the impact of viral infection on human gene regulation and human diseases. These ambitious goals will be achieved through the following aims: Aim 1. Create genome-wide maps of the virus-altered primary human cell epigenetic landscape. Aim 2. Globally discover vTR gene targets and impacted cellular phenotypes in primary human cells. Aim 3. Create a unique web resource enabling the discovery of vTR impacts on human diseases. We anticipate that this work will lead to the discovery of multiple causal human disease variants whose mechanisms act in a vTR and allele-dependent manner, leading to understanding of disease mechanisms and new therapeutic opportunities. Our approach provides a generalizable blueprint for the global characterization of pathogenic effects on host gene regulation in virtually any context, paving the way for future efforts aimed at understanding gene x environment interactions in the context of human diseases.


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 = $809,922 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Allergy and Infectious Diseases Research	000	5	9/1/2026	COMPETING CONTINUATION	$809,922
														Subtotal = $809,922

Grand Total All Awards = $809,922

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Virus-driven human gene misregulation in disease

Award Number: R01AI205712

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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