RR190087 — Cancer Prevention and Research Institute of Texas

Grant Information

Grant ID	RR190087
Awarded On	August 21, 2019
Title	Recruitment of First-Time, Tenure-Track Faculty Members
Program	CPRIT Scholar
Award Mechanism	Recruitment of First-Time, Tenure-Track Faculty Members
Institution/Organization	The University of Texas Southwestern Medical Center
Principal Investigator/Program Director	Gerta Hoxhaj
Cancer Sites	Leukemia, Myeloma
Contracted Amount	$2,000,000
Summary of Goals and Objectives	Goal 1: Determine if NADK is necessary for hematopoiesis or leukemogenesis. Objective 1: Generate conditional knockout NADK mouse model (NADKfl/fl); assess in vivo functions of NADK in normal tissues and cancer models. Objective 2: Determine if NADK is necessary for hematopoietic stem cell (HSC) maintenance or hematopoiesis. Objective 3: Determine if NADK is necessary for development or progression of acute leukemia in Mx-1-Cre;Flt3ITD;Tet2fl/fl or Mx-1-Cre;Ptenfl/fl mice. Objective 4: Determine metabolic consequences of NADK loss in leukemogenesis. Goal 2: Define molecular regulation and function of NADK in acute myeloid leukemia (AML)... Read More Goal 1: Determine if NADK is necessary for hematopoiesis or leukemogenesis. Objective 1: Generate conditional knockout NADK mouse model (NADKfl/fl); assess in vivo functions of NADK in normal tissues and cancer models. Objective 2: Determine if NADK is necessary for hematopoietic stem cell (HSC) maintenance or hematopoiesis. Objective 3: Determine if NADK is necessary for development or progression of acute leukemia in Mx-1-Cre;Flt3ITD;Tet2fl/fl or Mx-1-Cre;Ptenfl/fl mice. Objective 4: Determine metabolic consequences of NADK loss in leukemogenesis. Goal 2: Define molecular regulation and function of NADK in acute myeloid leukemia (AML). Objective 1: Identify key post-translational modifications on NADK in response to cancer-relevant metabolic changes including increases in levels of reactive oxygen species, modulation in nutrient and energy levels, and oxygen deprivation in AML cells. Objective 2: Determine functional significance and upstream mediators of the identified post-translational modifications of NADK. Objective 3: Assess functional relevance of post-translational modifications (including Akt-mediated phosphorylation of NADK) for lipogenesis, redox state, proliferation, and leukemogenesis. Goal 3: Systematic identification of novel NADK regulators and synthetic lethal interactions. Objective 1: Perform flow cytometry-based genome-wide CRISPR knockout screen in wild-type and NADK-knockout AML cells to identify regulators of NADK/cellular reducing power and genes that when mutated have a synthetic-lethal interaction with NADK loss. Objective 2: Characterize hits to identify regulators of NADK/cellular reducing power and determine their significance in AML cell growth. Objective 3: Identify synthetic lethal interactions between hits and NADK loss to inform mechanistic and co-targeting studies in AML. Read Less