Mitochondria are organelles that generate most of the energy in the cell. There is a gap in our understanding of how specific mitochondrial pathways are regulated to suit tissue-specific function and metabolism. The goal of this proposed research is to fill this knowledge gap and to reveal a previously unrecognized role for a nuclear receptor ERR?-dependent transcriptional program in kidney physiology and disease. Supported by our extensive preliminary data, we hypothesize that ERR? contributes to normal kidney function and renal disease by controlling mitochondrial and renal function in cooperation with kidney-specific transcription factors.
In Specific Aim 1, we will determine the essential role of ERR? in maintaining normal mitochondrial and renal function in vivo, using a novel mouse model. We will also investigate whether activation of the ERR? transcriptional program can improve kidney function in kidney disease models.
In Specific Aim 2, we will determine mechanistically how ERR? regulates renal mitochondrial and functional genes, employing state-of-the-art genomic approaches. Together, these studies will have a significant impact by enhancing our understanding of tissue specific mechanisms for maintaining mitochondrial function, and revealing a novel ERR? pathway in kidney function and the potential for therapies targeting ERR?.

Public Health Relevance

Mitochondrial dysfunction broadly contributes to diseases afflicting millions of people, including kidney disease, heart disease, obesity, diabetes, Alzheimer?s and Parkinson?s disease, cancer and aging. Our studies will fill the knowledge gap of how cells specialize their mitochondrial functions to suit specific cellular functions. These studies will also reveal a previously unrecognized role for ERR? in kidney function and disease, and the potential for therapies targeting ERR?.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK111495-01
Application #
9216368
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Li, Jing Jing; Liu, Jian; Lupino, Katherine et al. (2018) Growth Differentiation Factor 15 Maturation Requires Proteolytic Cleavage by PCSK3, -5, and -6. Mol Cell Biol 38:
Zhao, Juanjuan; Lupino, Katherine; Wilkins, Benjamin J et al. (2018) Genomic integration of ERR?-HNF1? regulates renal bioenergetics and prevents chronic kidney disease. Proc Natl Acad Sci U S A 115:E4910-E4919
Pei, Liming; Wallace, Douglas C (2018) Mitochondrial Etiology of Neuropsychiatric Disorders. Biol Psychiatry 83:722-730
Hu, Peng; Liu, Jian; Zhao, Juanjuan et al. (2018) Single-nucleus transcriptomic survey of cell diversity and functional maturation in postnatal mammalian hearts. Genes Dev 32:1344-1357
Emmett, Matthew J; Lim, Hee-Woong; Jager, Jennifer et al. (2017) Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge. Nature 546:544-548
Wang, Ting; Liu, Jian; McDonald, Caitlin et al. (2017) GDF15 is a heart-derived hormone that regulates body growth. EMBO Mol Med 9:1150-1164