Gladstone Institute of Cardiovascular Disease

Cholesterol and Heart Disease
• Recognized as world leaders for the last 30 years in studying apolipoprotein (apo) E, a plasma protein with a key role in cholesterol metabolism.
• Described how cholesterol-rich lipoproteins are taken up by the liver through their interactions with cell-surface receptors. – These findings contributed to the development of the cholesterol-lowering statin drugs.
• Established the importance in heart disease of cholesterol-rich lipoproteins originating from the diet and the intestine. – Presently a new cholesterol-lowering drug (Zetia) may reduce levels of these atherogenic lipoproteins.
• Determined the structure and function of apoE and its critical role in transporting cholesterol and triglycerides in lipoprotein particles in the blood. – Provided an understanding of how lipoproteins are removed from the blood and degraded.
• Defined the structure of three genetic forms of apoE. Two (apoE2 and apoE4) are associated with increased risk of heart disease, and one (apoE4) is associated with increased risk of Alzheimer's disease. ApoE3 is considered to be the “normal” form of the protein. – These findings provide basic knowledge linking apoE to specific disease mechanisms
• Determined the three-dimensional structure of various genetic forms of apoE. – Provides insight into how apoE disrupts normal processes related to both heart disease and neurodegenerative disorders.
• First to recognize the importance of apoE in neurobiology. – Provided the first evidence of the role of apoE in maintaining and protecting nerve cells.
• Identified the ACAT2 gene, which controls cholesterol-modifying fat synthesis. – Inhibitors of ACAT2 may be useful in lowering cholesterol levels and treating atherosclerosis.
• Discovered that low levels of HDL (the protective cholesterol-carrying lipoproteins or “good cholesterol”) in people of Turkish ethnicity are caused by a genetic factor. – This observation was used to mount a major public health program to stem an epidemic of heart disease in the more than 130 million people of Turkish origin. – Identification of genetic factors responsible for low HDL could lead to new drug targets to alter HDL levels in many people worldwide who have this risk factor for heart disease.
• Developed a mouse model for lipoprotein(a). An elevated blood concentration of this atherogenic lipoprotein is a strong predictor of heart disease. – This model will be useful for understanding how this lipoprotein causes heart disease. – Could lead to inhibitors that reduce atherosclerosis.

Obesity, Diabetes, and Heart Disease
• Discovered genes that control fat synthesis (DGAT enzymes). – This development could lead to therapeutics that inhibit DGAT1, which may be useful for treating obesity or diabetes. – Regulation of the DGAT gene in transgenic plants may be useful in increasing the content of rare oils or oils with commercial value.
• Discovered a triglyceride synthesis gene (called MGAT1) that is crucial for subcutaneous fat, but not for other fat deposits. – Inhibitors of MGAT1 could reduce excessive subcutaneous fat stores.
• Demonstrated that mice lacking the DGAT gene were resistant to obesity. – This finding could develop into an additional target for controlling obesity in humans.
• Demonstrated an association between variations in the DGAT1 gene and obesity in humans. – Increased understanding of obesity may lead to development of novel therapies.

Replacing Damaged Tissue and Organs
• Discovered the basis for some forms of heart failure, including the type with the fastest growing incidence in the U.S. – This discovery could lead to new ways to treat heart failure.
• Developed new tools for tissue engineering research. – These tools will facilitate the development of strategies to replace diseased tissue or cells in organs, such as the heart, brain, skin, and joints.

Vascular Wall Biology
• Cloned CCR2, a key cytokine receptor involved in regulating the entry of macrophages into the artery wall, where they accumulate cholesterol to form atherosclerotic plaques. – This development has great potential for new drugs to prevent atherosclerosis.

Infectious Disease
• Discovered that CCR2 also has a role in infection by anthrax and tuberculosis. – Holds the potential to combat infectious agents used by bioterrorists.

Aging and Cancer
• Discovered that two enzymes, called Zmpste24 and Icmt, are important for inserting special classes of proteins into membranes where they perform their normal function. – Disrupting the activity of Zmpste24 leads to a premature aging syndrome and, therefore, potentially may hold a key to understanding the aging process . – Disrupting the activity of Icmt inhibits the transformation of certain cells to cancerous cells and, therefore, inhibitors to it may be useful in blocking the development of certain forms of cancer.

Gladstone Institute of Virology and Immunology

HIV Immune Reconstitution—Rebuilding the Immune System in the Face of HIV
• Demonstrated that HIV not only kills blood lymphocytes (called T cells), which protect our bodies from infection, but also prevents their replacement, a phenomenon known as regenerative failure. – Fundamentally new approaches to preserving CD4 T-cell numbers in HIV-infected patients derive from this observation.
• Showed that interleukin 7 (interleukins are soluble proteins involved in cell-to-cell communication) and human growth hormone can boost T-cell replacement in HIV-infected patients. – The ability to enhance T-cell production in HIV-infected patients could greatly delay the onset of clinical disease.
• Initiated systematic studies to identify the types of immune responses that provide true protection against HIV infection. - These studies could fundamentally reshape the design of future HIV vaccines.
• Demonstrated that T-regulatory cells inhibit the cellular immune response to HIV. – These studies reveal an immune control mechanism that blunts the immune response to HIV.

HIV Pathogenesis—How Does HIV Work and How Can We Interrupt Its Growth?
• Identified how the HIV protein Vif defeats the action of a powerful anti-HIV factor normally produced by human T cells. – These studies have opened the door to the development of an entirely new class of anti-retroviral drugs.
• Developed a powerful cellular model system to study HIV latency (a state in which the virus is dormant or hidden in the cell). Latency is a significant reason why HIV infection cannot be cured by currently available therapies. – Understanding the molecular basis for HIV latency could lead to exciting therapeutic strategies to eradicate HIV in infected patients.
• Developed key insights into how the HIV Nef protein works to foster and accelerate the multiplication of the virus. – These studies could lead to new therapies for HIV-infected patients that block the critical disease-accelerating effects of HIV Nef.
• Showed that HIV infection of T cells in patients leads to cell-cycle arrest, which could contribute to accelerated death of CD4 T cells. Also showed that cell-cycle arrest is associated with dynamic changes in the structure of the nucleus. – These fundamental studies are helping to decipher how HIV infection leads to the death of CD4 T lymphocytes, an unsolved puzzle in HIV biology.
• Unraveled an entirely new mechanism for regulation of the NF-κB transcription factor, which functions as a master regulator of the immune and inflammatory responses. – These insights could lead to the development of new classes of anti-inflammatory drugs and could be applied differently to approach the problem of HIV latency.
• Developed a promising small animal model for the study of HIV and evaluation of new antiviral drugs and vaccines. – Full development of this small animal model could markedly accelerate the development and testing of new HIV therapeutics and vaccines.
• Exploited a novel model involving the grafting of human thymic and liver tissue into mice lacking immune systems to test candidate antiviral drugs. – This animal model effectively predicts whether drugs will work in HIV-infected patients and has been used preclinically to validate a number of different classes of drugs now approved by the FDA for use in infected patients.
• Identified key functions of the HIV Rev protein involving its action as both an inhibitor of viral RNA splicing and a facilitator of nuclear export of incompletely spliced viral RNAs. – These fundamental studies have expanded our understanding of the molecular mechanism of Rev action and could lead to new approaches to inhibiting the function of this key viral protein in the future.

HIV Therapy—Making What We Have Work Better
• Identified the beneficial declines in the fitness of viruses growing in HIV-infected patients receiving antiretroviral therapy. – These studies have completely revolutionized clinical management of HIV-infected patients who are “failing” on therapy.
• Developed an advanced mathematical model of the effects of increased distribution of antiretroviral medications to HIV-infected patients on the HIV epidemic in San Francisco. – This predictive model has served as the basis for a bold public health initiative in San Francisco through which antiretroviral therapy has been more broadly distributed to individuals who may not be fully compliant with their medications.
• Initiated an important clinical trial exploring whether anti-viral treatment can effectively block the spread of HIV to HIV-negative individuals at high risk for HIV infection. – This trial, if successful, could fundamentally change current approaches to curbing the expanding global HIV epidemic.

Gladstone Institute of Neurological Disease

Alzheimer's Disease, Parkinson's, and Related Conditions—What Causes These Conditions?
• Demonstrated that high levels of amyloid-β (Aβ) peptides disrupt the complex brain circuits in which memories are formed and stored.
  – Contributed to an important paradigm shift in the field, since the most widely held view before these findings was that large clumps of Aβ, known as amyloid plaques, were responsible for cognitive impairment in Alzheimer's disease.
• Showed that Aβ peptides can enhance the accumulation and toxicity of other disease-causing proteins, including α-synuclein, which plays a role in Parkinson's disease and so-called “dementias with Lewy bodies.”
  – These findings provide a molecular explanation for the frequent overlap between Alzheimer's disease and Parkinson's disease.
• Made the first observations implicating apoE in injury and repair of the nervous system.
  – This was the first link ever made between apoE and the nervous system .
• Demonstrated that apoE4 (the form of apoE associated with Alzheimer's disease) is much more susceptible to being broken down into neurotoxic fragments than other forms of apoE (apoE2 and apoE3) that do not impart increased risk of Alzheimer's disease on their carriers.
  – This finding likely provides the molecular basis for the link between apoE4 and Alzheimer's disease, which, until this discovery, had been elusive.

Alzheimer's Disease, Parkinson's, and Related Conditions—Potential Treatments
• Identified disease-causing activities of amyloid proteins associated with Alzheimer's disease and Parkinson's disease, as well as neuroprotective functions of amyloid precursor proteins.
  – Adds important information to the body of knowledge about the benefits and potential risks of targeting such proteins therapeutically.
• Discovered that cognitive deficits related to Alzheimer's disease are tightly linked to the depletion of calcium-dependent proteins in memory centers of the brain.
  – Provides new surrogate markers for preclinical trials and pinpoints biochemical pathways that could be targeted therapeutically.
• Provided compelling evidence that the neurotoxicity of Aβ peptides may critically depend on an enzyme called cathepsin B for which there are natural and pharmacological inhibitors.
  – This study has identified a new target for the treatment of Alzheimer's disease and potentially useful types of drugs for its therapeutic manipulation.
• Invented a powerful new technology (robotic microscope) to determine how mutations cause Huntington's disease, the most frequent inherited neurodegenerative disorder.
  – Since this technology can also be applied to Alzheimer's disease and Parkinson's disease, it paves the way for the development and screening of drugs for a variety of neurodegenerative disorders.
• At the molecular mechanism level, discovered reasons why apoE4 accelerates the onset of Alzheimer's disease.
  – Adds important new therapeutic targets to the field.
• Showed in transgenic mouse models that apoE4 is not only less neuroprotective than other apoE variants, but that it also actively interferes with their beneficial functions.
  – These findings provide critical guidance for the development of apoE-targeted drug treatments, by underlining the need to block the detrimental effects of apoE4.
• Isolated the neuron-specific enzyme that is most likely responsible for fragmenting apoE4 in a way that leads to disease.
  – Provides a promising new target for drug development.
• Identified mechanisms by which apoE4 can promote two hallmarks of Alzheimer's disease: amyloid plaques and neurofibrillary tangles.
  – Highlights how apoE4-targeted treatments could thwart diverse aspects of this illness.
• Identified molecules that regulate the outgrowth and branching of neuronal extensions, which are critical for the proper function and regeneration of neuronal cells.
  – Opens new avenues for repairing the nervous system when it has been damaged by disease.

Anti-Inflammatory Treatments, Including Aspirin—Will They Work?
• Demonstrated that some inflammatory responses in the brain actually counteract neurodegenerative disease (i.e., some component of inflammation may be beneficial in protecting the brain).
  – Suggests that the current therapeutic approach of suppressing the inflammatory machinery may be counterproductive and that it may be better to harness this internal defense system.

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