Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY/ABSTRACT The long-term goals of this proposal are two-fold: (i) understand the functional role of G0/G1 switch gene 2 (G0S2) during normal and obese hematopoiesis, and (ii) leverage that understanding for the development of new therapeutics to treat multiple obesity-related conditions. The prevalence of obesity in the United States has tripled over the past several decades, which has tremendous effects on overall health. Chronic inflammation, due to the overproduction of myeloid cells from hematopoietic stem cells (HSCs) of the bone marrow, is an established mechanism explaining the negative health impacts of obesity. Hematopoiesis is the process of blood cell production by HSCs residing in the bone marrow. Energy metabolism has emerged as an important regulator of HSC fate. Lipid metabolism, primarily fatty acid oxidation (FAO), was shown to aid in HSC self-renewal and differentiation. One important regulator of lipid metabolism is G0S2, a small 11 kDa protein that regulates multiple cellular functions, including intracellular lipolysis and oxidative phosphorylation. G0S2 contributes to triglyceride accumulation both indirectly through inhibition of lipolysis in adipose and liver tissue, and also directly through lysophosphatidic acyl transferase (LPAAT) enzymatic activity. However, while much is known about the role of G0S2 in highly metabolic cells, its role in normal blood cell development is unknown. We hypothesize that G0S2 LPAAT activity regulates lipid and energy during normal myeloid development. Specific Aim 1: Test the hypothesis that G0S2 regulates neutrophil development and function in normal but not obese mice. Utilizing mice maintained on a normal- versus high-fat-diet, we will assess the effects of altered G0S2 expression on the differentiation of murine HSCs in response to granulocyte-colony stimulating factor (G-CSF) both ex vivo and in vivo. We will utilize wild-type versus G0S2 knockout mice, and will test for differences comparing male versus female mice. Specific Aim 2: Test the hypothesis that G0S2 LPAAT activity contributes to myeloid development. We will investigate whether G0S2 LPAAT activity contributes to survival or differentiation of hematopoietic stem and progenitor cells. We will utilize bone marrow from G0S2 knockout mice for ectopic expression of wild-type versus mutant forms of murine G0S2. Resulting cells will be assessed for phenotypic changes both ex vivo and in vivo. We have formed a collaborative research team to rigorously establish the mechanistic role of G0S2 during myeloid development. Additionally, this R15 project will provide a unique training opportunity for graduate students in our MSc program. Texas Tech University Health Sciences Center at El Paso is a Title V Hispanic-Serving Institution located along the U.S./Mexico border, with a majority of our population identifying as Hispanic. This R15 will enhance the ability of our students to prepare for future jobs as research assistants, and will help them compete successfully for admission into MD and/or PhD education programs. Successful completion of the proposed experiments will be crucial for understanding the role of G0S2 and lipid metabolism during normal blood cell development, and will promote the careers of young minority students.
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