Document text
Principal Investigator: Rebecca K Davidson
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $73,828
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
This F32 proposal describes a comprehensive training and mentorship program for Dr. Rebecca Davidson,
a postdoctoral research fellow in the Department of Internal Medicine at the University of Michigan. Dr. Davidson
will participate in a rigorous training plan, guided by their mentor along with a multi-disciplinary advisory
committee. Their training program will include hands-on molecular, bioinformatics, and physiological training, as
well as mentored opportunities to engage in scientific writing, presentations, and grant applications. The ultimate
goal of this proposal is to best position Dr. Davidson for an independent and productive scientific career. Diabetes
is a global epidemic of increasing prevalence, where all forms of diabetes are linked by insufficient β-cell function
or mass to meet peripheral insulin demands. Type 2 diabetes (T2D) is a metainflammatory disease additionally
characterized by impairments in mitochondrial function and ultrastructure that contribute to overall disruption of
β-cell function. Mitochondria rely on their own 16.6 kilobase-pair circular genome to generate the machinery
required for oxidative phosphorylation. Recently, our group identified a reduction in mitochondrial DNA (mtDNA)
copy number in islets from T2D donors compared to islets from non-diabetic donors, indicating a disruption in
genome stability in diabetes. While mtDNA genome instability is implicated in several diseases, its impact on β-
cell dysfunction in diabetes has yet to be explored. The long-term objective of my project is to better
understand the molecular mechanisms underlying mitochondrial dysfunction in diabetic settings. My project
focuses on the β-cell-specific role of mitochondrial genome integrity on maintaining healthy mitochondrial
function to meet the energy demands of the β cell. My preliminary data indicate that the progressive accumulation
of deletions in β-cell mtDNA impair glucose homeostasis and β-cell function. Thus, I hypothesize that loss of
mtDNA genome integrity occurs in the presence of inflammatory stressors and contributes to mitochondrial and
β-cell failure in diabetes, which I will test through 2 Specific Aims. Aim 1 will determine the importance of mtDNA
genome integrity to β-cell function and survival in mouse models of β-cell-specific mtDNA disruptions. Aim 2 will
evaluate how diabetogenic stressors impact mtDNA genome integrity utilizing primary human islets and mouse
models of diabetes. Successful completion of these Aims will provide novel and critical insights into the
mechanistic contribution of mtDNA genome integrity on overall mitochondrial health and β-cell function required
to preclude diabetes development.
Terms: <21+ years old><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Advisory Committees><Age><Animals><Antimorphic mutation><Applications Grants><Attenuated><Beta Cell><Bio-Informatics><Bioenergetics><Bioinformatics><Blood Glucose><Blood Sugar><Causality><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell Survival><Cell Viability><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clonal Expansion><D-Glucose><DNA><DNA Damage><DNA Helicases><DNA Injury><DNA Unwinding Proteins><DNA copy number><DNA unwinding enzyme><Data><Deoxyribonucleic Acid><Development><Dextrose><Diabetes Mellitus><Diabetic mouse><Disease><Disorder><Dominant Negative><Dominant-Negative Mutant><Dominant-Negative Mutation><Dysfunction><Epidemic><Etiology><Failure><Free Radicals><Functional disorder><Generations><Genes><Genome><Genome Instability><Genome Stability><Genomic Instability><Genomic Stability><Glucose><Glucose Intolerance><Goals><Grant Proposals><Health><Heritability><High-Throughput Nucleotide Sequencing><High-Throughput Sequencing><Human><Humulin R><Immunofluorescence><Immunofluorescence Immunologic><Impairment><Inflammatory><Insulin><Insulin Cell><Insulin Resistance><Insulin Secreting Cell><Internal Medicine><Islet Cell><Ketosis-Resistant Diabetes Mellitus><Lead><Link><Maintenance><Maturity-Onset Diabetes Mellitus><Mentors><Mentorship><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic dysfunction><Mice><Mice Mammals><Michigan><Mitochondria><Mitochondria RNA><Mitochondrial DNA><Mitochondrial Diseases><Mitochondrial Disorders><Mitochondrial RNA><Modern Man><Molecular><Murine><Mus><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Nuclear><Oxidation-Reduction><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Pancreatic beta Cell><Pancreatic β-Cell><Patients><Pb element><Peripheral><Physiologic><Physiological><Physiopathology><Position><Positioning Attribute><Postdoc><Postdoctoral Fellow><Predisposition><Prevalence><Productivity><Proteins><Redox><Regular Insulin><Research><Research Associate><Respiration Disorders><Respiratory Disorder><Ribosomal RNA><Role><Slow-Onset Diabetes Mellitus><Spirometry><Stable Diabetes Mellitus><Staining method><Stains><Structure><Structure of beta Cell of islet><Subcellular Process><Susceptibility><T2 DM><T2D><T2DM><Task Forces><Technology><Testing><Thesaurismosis><Training><Training Programs><Transfer RNA><Translations><Transmission Electron Microscopy><Transplantation><Triplet Codon-Amino Acid Adaptor><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Universities><Writing><Xenograft Model><adult onset diabetes><adulthood><advisory team><ages><aging associated disease><aging related disease><attenuate><attenuates><beta cell development><blood glucose regulation><breathing disorder><career><causation><developmental><diabetes><diabetes mouse model><diabetic><diabetogenic><disease causation><disease of aging><disorder of aging><effective therapy><effective treatment><endocrine pancreas development><exposed human population><functional loss><genome integrity><genomic integrity><glucose control><glucose homeostasis><glucose regulation><heavy metal Pb><heavy metal lead><helicase><heteroplasmy><human exposure><improved><in vivo><insight><insulin resistant><insulin secretion><insulin tolerance><islet><islet development><ketosis resistant diabetes><maturity onset diabetes><metabolism disorder><mitochondrial><mitochondrial DNA mutation><mitochondrial dysfunction><mitochondrial genome><mouse model><mtDNA><mtDNA mutation><mtRNA><multidisciplinary><murine model><mutant><non-diabetic><nondiabetic><novel><oxidation reduction reaction><pancreas beta cell><pancreas β cell><pancreatic b-cell><pathophysiology><post-doc><post-doctoral><post-doctoral trainee><postnatal><programs><rRNA><research associates><respiratory dysfunction><response><selective expression><selectively expressed><social role><stressor><tRNA><transfer Ribonucleic acids><translation><transplant><type 2 DM><type II DM><type two diabetes><xenograft transplant model><xenotransplant model><β-cell><β-cells><βCell>