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The genetic basis for tissue specific sensitivities to mitochondrial stress

组织对线粒体应激特异性敏感性的遗传基础

基本信息

批准号：
8485607
负责人：
PATRICK H O'FARRELL
金额：
$ 34.07万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-19 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8485607
关键词：
Address Affect Alleles Biosensor Blindness Cause of Death Cells Chemicals Complex DNA Sequence Defect Development Diagnosis Disease Dose Drosophila genus Ectopic Expression Engineering Environment Environmental Risk Factor Experimental Models Exposure to Eye Failure Fertility Functional disorder Gene Mutation Genes Genetic Genetic Engineering Genetic Models Genetic Polymorphism Goals Growth Health Healthcare Human Hypertrophy Lead Mammals Mitochondria Modeling Mutate Mutation Mutation Detection Nature Nuclear Oligomycins Oxidative Phosphorylation Parkin gene Pharmaceutical Preparations Phenotype Point Mutation Population Protein Isoforms Proteins Provider RNA Interference Respiratory Chain Role Rotenone Specificity Sterility Stress Syndrome Testing Testis Tissues Toxic effect Toxicant exposure Toxin Ursidae Family Work base cell growth cell transformation cell type chemical genetics cytochrome c cytochrome c oxidase empowered environmental chemical fly improved inhibitor/antagonist male mitochondrial dysfunction mitochondrial genome mutant novel strategies prevent research study sensor stressor tool toxicant transdetermination tumor progression

项目摘要

ABSTRACT Our goal is to understand how mutations and inhibitors that disrupt general mitochondrial functions can cause syndromes with marked tissue specificity. We are developing new experimental models in which we can bring the powerful genetic tools in Drosophila to bear on this question. We will test whether the tissue specificity of genetic and chemical stressors occurs because they target interactions between general mitochondrial functions and tissue specific genes. A particular mutant of Drosophila Cytochrome oxidase subunit 1 is male sterile, and otherwise normal. We hypothesize that this highly specific phenotype is the result of a failure of this allele to work conjunction with a testis specific isoform of one of the other respiratory chain proteins. Indeed, ectopic expression of the somatic version of Cytochrome c in the testis suppresses the sterility phenotype. The proposed experiments will rigorously test whether this sterility is due to a specific deficit in the partnership of the mutant Cytochrome oxidase and the testis specific isoform of Cytochrome c. Additionally, we will engineer the fly eye as a biosensor for disruption of isoform-specific interactions of mitochondrial functions, and will apply it to identify mutations and chemicals interfering with these interactions. We will also explore tissue specificity resulting from a synergy of two defects, where a tissue specific defect sensitizes a tissue to diverse genetic and chemical stressors. Eye specific knockdown of E2F compromised growth to produce a slightly reduced eye. It also sensitized the eye to mitochondrial stress. A low dose of oligomycin that is without notable effect in other tissues, synergizes with E2F:RNAi in the eye to produce tissue transformations (e.g. antennae growing out of the eye) and hypertrophy. We hypothesize that this dysgenesis/hypertrophy relies on two inputs with a biologically universal relationship. Any mutation that inhibits growth of a specific tissue creates a selective environment favoring cells that can escape the growth limitation by transforming to another cell type (transdetermination). A second stress that destabilizes developmental fate would produce the fodder for this selection. Mitochondrial stress appears to provide this destabilizing input. We will test this model and screen for natural mutations and environmental chemicals contributing to the synergizing inputs. Since mammals express numerous proteins as tissue-specific isoforms, they carry many genes that can mutate to create a selection for transdetermination. Without synergizing input, these mutations would have little impact and could accumulate. Thus, we suspect that the human population has a large and insidious pool of "polymorphisms" that creates a diversity of chemical sensitivities. Recognition of sensitizing mutations should empower application of DNA sequencing to personalized health-care.

摘要