My long-term research goal is to understand the role of molecular chaperones in protein homeostasis and how proteostasis influences healthspan and longevity. Molecular chaperones, namely heat shock proteins (HSPs), play a key role in maintaining protein quality, preventing protein unfolding and aggregation and influencing the rates of protein degradation via either the proteasome or autophagy. During aging, most organisms have a greater load of damaged or misfolded proteins to target for degradation. This condition is exacerbated by a decline in the efficacy of proteolytic machinery and leads to an accrual of the aggregation-prone cytotoxic proteins that underlie several age-associated pathologies (e.g., Alzheimer’s disease, Parkinson’s disease, sarcopenia). As such, the loss of protein homeostasis is considered to be one of the ‘hallmarks of aging’.
I have recently discovered that heat shock protein 25kDa (HSP25) correlated with maximum lifespan potential in rodent muscle and liver tissue. The mechanisms and regulatory processes by which HSP25 is responds to stress within a cell and this regulation influences both cellular and organ health and lifespan is unknown and presents a gap of knowledge in the field of chaperone biology. In Project I, we will investigate the role of HSP25 on longevity and protein homeostasis using primarily the Caenorhabditis elegans worm model system. In Project II, my laboratory will pursue the mechanism behind HSP25 regulation and its potential role in proteolytic mechanisms during stress using vertebrate cell culture and tissues. Finally, in Project III we will examine the physiological ramifications of changes in HSP25 expression focusing on its role in muscle function in vertebrate animals.
Rodriguez KA, Valentine JM, Kramer DA, Gelfond JA, Kristan DM, Nevo E, Buffenstein, R. Determinants of rodent longevity in the chaperone-protein degradation network. Cell Stress Chaperones. 2016 May; 21(3):453-66. doi 10.1007/s12192-016-0672-x. PMID: 26894765.
Rodriguez KA, Li K, Nevo E, Buffenstein R. Mechanisms regulating proteostasis are involved in sympatric speciation of the blind mole rat, Spalax galili. Autophagy. 2016 April 2; 12(4) 703-04. doi: 10.1080/15548627. PMID: 27050459
Triplett JC, Tramutola A, Swomley A, Kirk J, Grimes K, Lewis K, Orr M, Rodriguez K, Cai J, Klein JB, Perluigi M, Buffenstein R, Butterfield DA. Age-related changes in the proteostasis network in the brain of the naked mole-rat: Implications promoting healthy longevity. Biochim Biophys Acta. 2015 Oct; 1852(10 Pt A):2213-24. doi: 10.1016/j.bbadis.2015.08.002. PMID: 26248058.
Li K, Hong W, Jiao H, Wang GD, Rodriguez KA, Buffenstein R, Zhao Y, Nevo E, Zhao H. Sympatric speciation revealed by genome-wide divergence in the blind mole rat Spalax. Proc Natl Acad Sci U S A. 2015 Sep 22; 112(38):11905-10. doi: 10.1073/pnas.1514896112. PMID: 26340990.
Rodriguez KA, Osmulski PA, Pierce A, Weintraub ST, Gaczynska M, Buffenstein R. A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition. Biochim Biophys Acta. 2014 Nov; 1842(11):2060-72. doi: 10.1016/j.bbadis.2014.07.005. PMID: 25018089.
Rodriguez KA, Dodds SG, Strong R, Galvan V, Sharp ZD, Buffenstein R. Divergent tissue and sex effects of rapamycin on the proteasome-chaperone network of old mice. Front Mol Neurosci. 2014 Nov 4; 7:83. doi: 10.3389/fnmol.2014.00083. eCollection 2014. PMID: 25414638.