Shireesh Srivastava
srivas14(at)msu.edu
1103 Engineering Building
517.432.2346
Hometown: New Delhi, India
Undergraduate Institution:
University of Delhi, India
Graduate Institution:
Michigan State University (East Lansing), Indian Institute of Science
(Bangalore, India) and Devi Ahilya University (Indore, India)
Interests: Research: Biochemical Engineering, Metabolic
Engineering, Biotechnology
Personal: Movies, Music, Travel
Project title: Integration of physiological,
metabolic and genetic information to identify mechanisms of free fatty
acid toxicity to hepatoma cells
Project Description: The development of novel
high-throughput techniques has made it possible to identify the global
metabolic and genetic responses of the cells under a variety of
conditions. The challenge is to efficiently analyze and integrate the
multi-source high-throughput data to generate novel information about
cellular responses. My research is an effort in that direction. The
research involved characterization of physiological, global metabolic and
genetic alterations caused by different types of free fatty acids (FFAs)
and tumor necrosis factor alpha (TNF-a) in the context of lipotoxicity,
and the development of systems-biology frameworks to integrate
multi-source information.
In the first part of the research, the toxicity of different types of free
fatty acids was investigated. Among the different types of FFAs, only
saturated FFA (palmitate) was toxic to the cells. Interactive effects of
palmitate and TNF-a were observed on the toxicity. The reactive oxygen
species (ROS) mediating the palmitate-cytotoxicity were identified to be
hydrogen peroxide and hydroxyl radicals. In the next part, the differences
in the metabolism of the cells in response to different types of FFA were
investigated by applying metabolic flux analysis (MFA). It was identified
that palmitate reduced the synthesis of glutathione by reducing cysteine
uptake, caused by a reduction in the levels of cystine transporter xCT.
Supplementing cysteine to the cells reduced the toxicity significantly.
The global genetic changes caused by exposure to FFAs and TNF-a were
identified by microarray analyses. Two novel methods were developed to
integrate genomic and metabolic/ physiological information. In the first
method, the genes that regulate multiple cellular responses were
identified by the dual response genetic algorithm partial least squares
(GA/PLS) analysis. This method identified that NADH dehydrogenase and
mitogen activated protein kinases (MAPKs) regulate cytotoxicity and TG
accumulation. These predictions were experimentally verified. Finally, a
novel Bayesian regression mixture model-based framework was developed to
incorporate the gene ontology (GO) information to select the genes that
could discriminate between the subpopulations. Thus, in this research,
multiple alterations responsible for mediating palmitate-toxicity to
hepatoma cells were identified and novel frameworks were developed to
integrate multi-source high-throughput information.
PI: Christina Chan