Alzheimer's disease (AD) affects 5.5 million Americans producing cognitive deficits and mortality. Thereis no treatment for AD, thus, development of interventions to slow or reverse AD symptoms is a critical area ofresearch. Furthermore, AD is difficult to detect until substantial neurodegeneration has already occurred. Thisproposal investigates proteasome function both as an intervention to AD symptoms and as a tool for earlystage diagnosis in peripheral tissues. A key symptom of AD is proteostatic dysfunction.

Despite the increasing numbers of aging individuals in our country, there is little understanding of theinteraction between the mechanisms of aging and the pathophysiology of age-related diseases. Research inthis area is essential since age is the largest risk factor for various diseases. If this relationship can be resolved,it would open new avenues for therapeutic interventions to treat/prevent age-related diseases. Oxidative stressis one of the fundamental biological processes that link aging and age-related diseases.

Neural stem cell/progenitors cells give rise to mature neurons, astrocytes and oligodendrocytesthroughout life. However, neurogenesis rapidly declines during aging and the mechanism forage-dependent neural stem cell dysfunction is not clear. The ventricular-subventricular zone (V-SVZ), lining the lateral ventricle, is home to the largest pool of neural stem cells in the murinebrain. We have found that microglia, the innate immune cells of the brain, are prominentlypositioned throughout the young and aged V-SVZ niche.

Emerging evidence supports the proposition that the mitochondrial respiratory chain (MRC) functions viaorganized multicomplex structures called supercomplexes. However the dynamics and regulation ofsupercomplex assembly have not been fully investigated. In particular, hardly any regulatory protein factorsinvolved in supercomplex assembly have been identified. Our long term goal is to understand the dynamics ofmitochondrial respiratory machinery and its underling regulatory mechanism.

This proposal combines a team with expertise in aging, tumor immunology, tumor immunotherapy, specificgenetically modified animal models and early phase clinical trials with a computational team having greatexpertise in analyzing and modeling aging of the immune system.

A distinguishing trait of heme enzymes is that a high-valent iron-oxo species is the common oxidant for mediating a remarkable array of oxidation reactions. However, the conundrum is that each enzyme in general only promotes a specific type of reaction. How the reaction type is determined after formation of the key oxidant remains to be an unsolved question. Answers to this question have implications for our fundamental understanding of enzyme catalysis as well as de novo enzyme design and protein engineering.

BACKGROUND