(1) The Oxygen Ledger: Oxygen is the substrate for over 400 known biochemical reactions, surpassing even ATP and NADH. When oxygen levels fall below a tissue’s buffering capacity, there are devastating effects on health and survival. Notably, the leading causes of death in developed nations are due to impaired oxygenation – heart disease, stroke, and respiratory disease. Our goal is to understand which metabolic processes fail as a function of oxygen tension and which pathways are successfully rewired to cope with variations in oxygen levels.
(2) Turning the Oxygen Dial as a Therapy: While small molecules and biologics are the most common forms of therapy, we believe we have uncovered a new mode of treating metabolic disorders. We now hope to extend our findings to additional inborn errors of metabolism, as well as more common metabolic disorders. By turning the oxygen dial to low or high oxygen, we hope to understand and treat additional disease conditions.
(3) The Role of Oxygen in Aging Physiology: Oxygen is both a necessary and toxic substrate for aerobic life, allowing for vital ATP production, while simultaneously generating damaging free radicals. Epidemiological studies suggest a close relationship between longevity and hypoxia, with 7 of the 10 longest-lived US counties found at the high altitudes of Colorado. Moreover, species that are particularly hypoxia and anoxia-tolerant (e.g. naked mole rat, African painted turtle, etc.) tend to be the longest-lived. Thus, understanding the interplay between oxygen and the (cellular and physiological) hallmarks of aging will improve our understanding of the aging process and offer hope for new therapies for age-associated conditions.
1. M. Ferrari*, I. H. Jain*, Goldberger, O…V. K. Mootha**, W.M. Zapol**. Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome. PNAS, 114 (21), E4241-E4250 (2017). [*equal contribution] (PDF) (PubMed)
News: Oxygen Deprivation Counters Deadly Mitochondrial Disease in Animals
Perspective: Mitochondrial Disease Therapy from Thin Air
3. I. H. Jain*, V. Vijayan*, E.K. O’Shea. Spatial ordering of chromosomes enhances the fidelity of chromosome partitioning in cyanobacteria. PNAS, 109 (34), 13638-13643 (2012). [*equal contribution] (PDF) (PubMed)
5. A. D. Hoptak-Solga, S. Nielsen, I. H. Jain, R. Thummel, D. Hyde, and M. K. Iovine. Connexin43 (GJA1) is required in the population of dividing cells during fin regeneration. Developmental Biology, (2008)
6. I. H. Jain, C. Stroka, J. Yan, W. Huang, M. K. Iovine. Bone growth in zebrafish fins occurs via multiple pulses of cell proliferation. Developmental Dynamics, 236, 2668-2674 (2007)
7. A. Sharma, H. Jain, J. O. Carnali, I. H. Jain. Inhomogeneous evolution of a glass surface via free, rapid expansion. Applied Physics Letters, 83, 2802-2804 (2003)
Isha received her undergraduate degree in Chemical and Physical Biology from Harvard University. There, she worked in the lab of Erin O’Shea on bacterial chromosome segregation. Subsequently, she joined the Harvard-MIT Program in Health Sciences and Technology. During her PhD, she worked in the labs of Vamsi Mootha and Warren Zapol, where she made the discovery that hypoxia could serve as a therapy for mitochondrial disorders. Isha is currently a UCSF Sandler Faculty Fellow in the Department of Physiology.