Dr. Sood's primary research interest is to perform functional genomic analysis of genes to understand their role in normal development and disease processes by applying cutting-edge molecular biology tools, genomic technologies and zebrafish as a model system. In the Oncogenesis and Development Section (ODS), her research focus is the genetic regulation of hematopoiesis and genetic and genomic events that lead to leukemogenesis, particularly acute myeloid leukemia involving chromosomal rearrangements of the core binding factors.
For studies aimed at understanding the genetic regulation of hematopoiesis, Dr. Sood performed reverse genetic screens in zebrafish to generate novel mutants for several important hematopoietic genes. Through the study of mutations in gata1 and runx1, two of the major transcriptional regulators of primitive and definitive hematopoiesis, respectively, Dr. Sood has demonstrated differential requirements of these genes during distinct waves of hematopoiesis. These mutants provide tools for understanding the mechanism of hematopoiesis, particularly emergence and differentiation of hematopoietic stem cells and developing new therapeutics for blood disorders by high-throughput chemical screening.
Animal models play a critical role in understanding the genetic regulation of normal development and disease pathophysiology. Recent developments in sequencing technologies have allowed researchers to apply whole exome sequencing to identify candidate genes with putative disease-causing variants in patients with rare diseases. To identify the causative gene from this list of candidate genes requires cell-based and in vivo animal models. Zebrafish as a vertebrate model for functional genomics gained popularity in the last decade with the development of technologies for forward and reverse genetic screens to identify genotype-phenotype correlations.
Dr. Sood, with advice from Paul Liu, Ph.D., and Shawn Burgess, Ph.D., established the NHGRI Zebrafish Core in 2005 to facilitate functional genomics analysis of candidate genes by NHGRI investigators. As the director of the Zebrafish Core, Dr. Sood's work includes management of the day-to-day core activities and implementation of new approaches to increase the throughput and quality of the core services while reducing cost. Under Dr. Sood's guidance, the core staff provides services (microinjections, whole mount in situ hybridization, generation of genetic mutants and transgenic lines, cryopreservation, imaging, in vitro fertilization to recover frozen lines), training (handling and breeding, monitoring embryo development, imaging, whole mount in situ hybridization) and maintains several commonly used wild type, mutant and transgenic zebrafish lines.
Since its inception, the Zebrafish Core has adopted new technical developments in the field of zebrafish research and developed protocols and resources so that all NHGRI investigators can apply cutting-edge methodologies to their research. In particular, the core developed efficient high-throughput protocols for both random and targeted mutagenesis approaches to generate genetic mutants in zebrafish. For random mutagenesis, >3,000 males heterozygous for N-ethyl-N-nitrosourea (ENU)-induced random point mutations were generated and screened by Targeting Induced Local Lesions IN Genomes (TILLING) () to identify missense and truncation mutations in several genes.
For targeted mutagenesis, Dr. Sood has developed cost-effective methods to efficiently generate knockout alleles using new genome-editing tools, such as zinc-finger, tal-effector and CRISPR/cas nucleases (ZFNs, TALENs and RGENs). The core applies a two-pronged approach to the functional analysis of candidate genes. First, a transient knockdown model is established using antisense morpholinos to investigate the effect on embryonic development. In parallel, genetic mutants are generated for evaluation of larval and adult phenotypes. To date, Dr. Sood has generated mutant zebrafish lines for over 50 genes involved in diverse cellular and developmental processes such as DNA repair, hematopoiesis, immunity, metabolic diseases, cancer and rare phenotypes studied by the NIH Undiagnosed Diseases Program. Upon generation of mutant lines, the zebrafish core helps researchers with in depth phenotype analysis by morphological, histological and biochemical assays.
Zebrafish Core Members
Kevin Bishop, B.S., Biologist
Blake Carrington, B.S., Biologist
Posted: January 6, 2015