Comprehensive characterization of variants underlying heart and blood diseases with crispr base editing
Active Cooperative Agreement Awarded Last action
- Award ID
- UM1HG012010
- Recipient
-
The General Hospital Corporation UEI FLJ7DQKLL226
- Awarding agency
-
National Human Genome Research Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $20,115,508
Award facts
- Assistance listing
- 93.172 Human Genome Research
- Completion date 89% complete
- Originally
- Funding
-
- $19,082,359.00 Federal
- $1,033,149.00 Non-federal
- Place of performance
- Boston, MA 02114, USA
Award details come from USAspending.gov.
Description
- Abstract
- How genomic variation influences cellular function is a fundamental problem with tremendous importance for human disease. While IT has traditionally been difficult to study the effects of specific sequence variants in an experimentally controlled manner, precise genome editing technologies such as crispr base editing enable "writing" of trait-associated variants to cells to unravel their function. In this proposal, we will perform multi-modal genome editing-based functional characterization of a total of 72,000 genomic variants associated with cardiovascular diseases (cvds) and hematological traits. CVD and blood traits are uniquely suited to functional dissection because cardiovascular (coronary artery disease, high blood pressure, dyslipidemia) and blood traits have among the best-powered multi-ethnic gwas of any traits, and a substantial component of trait variability can be captured in cellular assays that can be scaled to perform high-throughput screening. We have assembled an interdisciplinary team of world-class experts to provide a generalizable pipeline to unravel the functional impact of CVD and blood trait variants by integrating: (1) rich and ancestry-diverse human genetic discoveries, (2) broadly targetable crispr base editors and efficient delivery to primary human cells, (3) high-content assays to profile phenotypes at the levels of chromatin, gene expression and cellular function, and (4) computational methods to design, interpret, visualize, and share experimental results. In aim 1, we will employ a robust, three-tiered variant prioritization scheme that incorporates evidence for disease association from large, multi-ethnic gwas as well as probability of causality to nominate variants for functional assessment. Through this scheme, we will select variants associated with red blood cell and neutrophil traits, coronary artery disease, blood pressure, and HDL and LDL cholesterol that span a range of allelic frequencies and likely causality to test in high-throughput cellular assays. In aim 2, we will perform systematic cellular phenotype-based screens using base editors to install candidate variants as well as crispr epigenetic inhibition and activation to explore variant-containing regulatory elements. We will use eight established, scalable cellular phenotypic readouts, each of which will enable US to assess which of 12,000 variants and variant-centered elements alter CVD and blood trait-associated cellular phenotypes. We will additionally employ a high-throughput, genome-integrated chromatin accessibility assay to assess which variants alter chromatin accessibility in trait-relevant cell lines. We will follow up with targeted single cell RNA-SEQ of 5,600 variants in primary cells from donors of different SEX and ethnicity. In aim 3, we will produce a catalog of validated variants and their association with phenotypes for each of the proposed screens. We will collaborate with other igvf groups to utilize these data to optimize models that predict functional variants, regulatory elements and disease-causing biological mechanisms, ultimately leading to more complete understanding of the genetic underpinnings of cardiovascular and blood disease risk.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $1,701,223 | $0 | |
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| Amendment | $1,928,820 | $0 | |
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| Amendment | $1,033,149 | $0 | |
| Original award | $1,033,149 | $1,033,149 |
Show all 25
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Brigham & Womens Hospital Inc. | $379,354 | |
| The Children's Hospital Corporation | $375,303 | |
| Icahn School Of Medicine At Mount Sinai | $93,824 | |
| Institut De Cardiologie De Montreal | $758,672 | |
| Brigham & Womens Hospital Inc. | $1,708,186 | |
| Icahn School Of Medicine At Mount Sinai | $505,288 | |
| The Children's Hospital Corporation | $2,145,845 |
Quick answers
Who received award UM1HG012010?
UM1HG012010 was awarded to The General Hospital Corporation by National Human Genome Research Institute (National Institutes of Health) on September 1, 2021.
How much is award UM1HG012010 worth?
$20,115,508 has been obligated on UM1HG012010: $19,082,359 in federal funding and $1,033,149 in non-federal funding.
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