CSB Faculty
Brian Herman, Ph.D.
Professor
Chancellor's Health Fellow in Collaboration, UT System
Special Assistant to the President, UT Health Science Center
University of Connecticut Medical School, 1980
AAB 424
(210) 567-0397
HERMANB@UTHSCSA.EDU
Visit Dr. Herman's Lab on the lablife website.
Dr. Herman currently serves as a UT System Chancellor's Health Fellow in Collaboration and as a Full Professor in the Department of Cellular & Structural Biology. Dr. Herman received his undergraduate degree in Biology from Adelphi University. He received his doctorate from the University Of Connecticut Health Science Center and undertook postgraduate training at Harvard medical School. Following the completion of his postgraduate training, he joined the faculty at the University of North Carolina at Chapel Hill School of Medicine. He assumed the position of Professor & Chair of the Department of Cellular & Structural Biology at the UT HSC in June 1998, serving in this capacity until October 2004, when he assumed the position of Vice President for Research at the UT HSC. Dr. Herman is a past recipient of an American Cancer Society Faculty Research Award, (1991-1995), the Dozer Fellowship from Ben Gurion University, Israel, (1998) and an NIH (National Institute of Aging) Method to Extend Research in Time (MERIT) Award (1994-2004). In 2004, Dr. Herman received the UTHSCSA Presidential Distinguished Scholar Award. In 2005, he received a second NIH (National Institute of Aging) Method to Extend Research in Time (MERIT) Award (2005-2015). He serves on a number of editorial boards, including his current third five-year term on the Journal of Biological Chemistry. Dr. Herman has served on multiple NIH and NSF study sections including a four-year term on the NIH Cell, Development and Function-2 study section, two of which he served as Chair of the study section. Dr. Herman is an internationally renowned researcher in the field of cell death/apoptosis and the applications of optical imaging technologies to the study of cellular, tissue and organismal physiology and pathophysiology. He has published over 450 peer reviewed papers, book chapter and abstracts, edited four books, and he has trained 26 students and 27 postdoctoral fellows over his scientific career.
Research Interests:
Our research focuses on the relationship between apoptosis (cell suicide) and aging. Over the past decade, our work has focused on understanding the role of oxidative stress in the etiology of aging. This collaborative effort has resulted in significant research breakthroughs and successful applications for external funding by the participating investigators, as well as significant numbers of peer reviewed publications. Amongst our findings is that normal aging is accompanied by up regulation of the activity of the intrinsic pathway of apoptosis. Importantly, we have generated exciting preliminary data that implicates a specific cysteine protease, caspase-2, as a potential mediator of mitochondrial oxidative stress in an age-dependent fashion. Our data has led us to hypothesize that caspase-2 modulates mitochondrial oxidative stress-induced apoptosis in hepatocytes, neurons and other cells and that such apoptosis affects aging in a tissue specific fashion.
In particular, the lab is pursuing two projects. The first of these is to determine the role of caspase-2 in age-related osteoporosis. We have previously shown that male casp-2-/- mice manifest severe osteopenia as they age. Briefly, these mice exhibit decreased total body, vertebral, and femoral bone mineral density (BMD), increased uptake of 99m-technecium-tin-methylene-diphosphonate, increased presence of deoxypyridoniline in urine and decreased bone volume (BV/TV) - symptoms characteristic of osteopenia. Micro-computed tomography and histomorphometry reveal an abnormal growth plate, lower numbers of secondary ossification centers, decreased cortical bone thickness and decreased trabecular numbers. In vitro cultures of osteoclasts show that caspase-2 is expressed only on exposure to mitochondrial oxidative stress and that osteoclast numbers increase on exposure to inhibitors of caspase-2. In addition, CSF-1 (inducer of osteoclast differentiation) expression is enhanced in casp-2-/- bone. Taken together, these data implicate a role for caspase-2 in modulating osteoclast survival. We hypothesize that caspase-2 can function as a sensor of oxidative stress in bone and mediates apoptosis of osteoclasts in response to increased age-dependent oxidative stress in bone. Because loss of caspase-2 is associated with increased autophagy and autophagy plays a critical role in osteoclast function, we further hypothesize that caspase-2 modulates osteoclast activity. A majority of anti-osteoporosis medicines act by inducing osteoclast apoptosis by unknown mechanisms that may involve caspase-2. Understanding the mechanism of osteoclast apoptosis at advanced ages is an issue of high clinical importance.
The second project is to determine the role of caspase-2 in the neurodegenerative disorder Parkinson's disease. We have recently shown that dopamine and tyrosine hydroxylase (TH) levels in casp-2-/- mice exposed to 1-methyl-4-1,2,3,6-tetrahydropyridine (MPTP) were unaffected as compared to significant decreases observed in wild type (WT) mice. Furthermore, primary mesencephalic neuronal cultures as well as TH-positive neurons in vivo in casp-2-/- mice were resistant to MPP+-induced or MPTP-induced apoptosis, respectively. These results suggest that caspase-2 may play a vital role in modulating the MPTP-induced damage to the nigrostriatal dopaminergic system.
These studies are both significant and innovative, as they address the mechanisms of a fundamental biological process, apoptosis, in a number of normal and pathological activities of organisms and provide important information about the relationship between oxidative stress, apoptosis and aging in a tissue specific fashion. Our studies have led to the development of a number of transgenic, knockout and double mutant mouse models that coupled with novel imaging approaches are used to test the hypothesis that cellular and organismal response to oxidative stress plays a major role in the rapidity of age-dependent changes in healthspan partially through the regulation of apoptosis.
Figure 1:
(a) 3D-rendering of images from micro-computed tomography of WT and casp-2-/- (KO) bone. Note that KO bone is more porous.
(b) Caspase-2 expression is observed in WT osteoclasts only after treatment with the mitochondrial oxidative stress-inducing agent, rotenone (ROT); absence of staining in KO osteoclasts demonstrates antibody specificity.
Figure 2:
(a) Caspase-2 is essential for ROT-induced neuronal apoptosis. WT and casp-2-/- cortical neurons were treated with 0.3 µM ROT for 36 or 72 hours. Cell viability was determined using calcein-AM (stains live cells green), and propidium iodide (stains dead cells red). All nuclei were stained blue with Hoechst-33258. Histogram indicates counts; *, p< 0.05
(b) Loss of caspase 2 protects TH-positive neurons from MPP+-induced apoptotic cell death. WT and casp-2-/- mesencephalic neuronal cultures were treated with 10 µM MPP+ for 48 hours and apoptotic cells counted; *, p<0.001
Research Techniques:
In vivo optical imaging
Immunohistocytochemistry
Molecular biology
Mouse genetic models of aging
Bioassays
Biochemistry
Histology
Immunohistochemistry
PUBLICATIONS:
Tiwari M, Herman B, Morgan WW. (2011)
A knockout of the caspase 2 gene produces increased resistance of the nigrostriatal dopaminergic pathway to MPTP-induced toxicity. Exp Neurol. 2011 Jun;229(2):421-8.
Tiwari M, Lopez-Cruzan M, Morgan WW, Herman B. (2011) Loss of caspase-2-dependent apoptosis induces autophagy after mitochondrial oxidative stress in primary cultures of young adult cortical neurons. J Biol Chem. 2011 Mar 11;286(10):8493-506.
Ramanujan VK, Herman BA. (2008) Nonlinear scaling analysis of glucose metabolism in normal and cancer cells. J Biomed Opt. 2008 May-Jun;13(3):031219.
Ramanujan VK, Jo JA, Cantu G, Herman BA. (2008) Spatially resolved fluorescence lifetime mapping of enzyme kinetics in living cells. J Microsc. 2008 Jun;230(Pt 3):329-38.
Zhang Y, Padalecki SS, Chaudhuri AR, De Waal E, Goins BA, Grubbs B, Ikeno Y, Richardson A, Mundy GR, Herman B. (2007) Caspase-2 deficiency enhances aging-related traits in mice. Mech Ageing Dev. 2007 Feb;128(2):213-21.