Biomedical Informatics about Genes - Essay Example

BIOMEDICAL INFORMATICS Genes are the units of heredity in living organisms. They are en d in the organism's genetic material (usually DNA or RNA), and control the development and behavior of the organism. During reproduction, the genetic material is passed on from the parent(s) to the offspring. Genetic material can also be passed between un-related individuals (e.g. via Transfection, or on viruses). Genes encode the information necessary to construct the chemicals (proteins etc.) needed for the organism to function. Ref: Richard Dawkins (1990). The Selfish Gene, Oxford University Press. ISBN 0192860925. Parkinson's disease Research Plan Understanding Parkinson's Disease Parkinson's disease is one of a larger group of neurological conditions called motor system disorders. Historians have found evidence of the disease as far back as 5000 B.C. It was first described as "the shaking palsy" in 1817 by British doctor James Parkinson. Because of Parkinson's early work in identifying symptoms, the disease came to bear his name. In the normal brain, some nerve cells produce the chemical dopamine, which transmits signals within the brain to produce smooth movement of muscles. In Parkinson's patients, 80 percent or more of these dopamine-producing cells are damaged, dead, or otherwise degenerated. This causes the nerve cells to fire wildly, leaving patients unable to control their movements. Symptoms usually show up in one or more of four ways: tremor, or trembling in hands, arms, legs, jaw, and face rigidity, or stiffness of limbs and trunk bradykinesia, or slowness of movement Postural instability or impaired balance and coordination. This diagram of the brain shows several structures related to Parkinson's disease. Basal ganglia affect normal movement and walking; substantia nigra are types of basal ganglia that produce the neurotransmitter dopamine, which sends messages that control muscles. The globus pallidus is part of a larger structure connected to the substantia nigra affecting movement, balance and walking. The thalamus serves as a relay station for brain impulses, and the cerebellum affects muscle coordination. Though full-blown Parkinson's can be crippling or disabling, experts say early symptoms of the disease may be so subtle and gradual that patients sometimes ignore them or attribute them to the effects of aging. At first, patients may feel overly tired, "down in the dumps," or a little shaky. Their speech may become soft and they may become irritable for no reason. Movements may be stiff, unsteady, or unusually slow. Ref : www.fda.gov/fdac/features/1998/498_pd.html - Basic PD research over the last several decades, including genetics, molecular and cellular biology, characterization of neural circuitry, brain anatomy, and neurochemistry, has formed the basis of therapeutic research being currently pursued for PD. While the causes of PD are still not fully understood, the most prevalent theories suggest that toxic accumulation of protein in cells, dysfunctional protein clearance, and oxidative stress that leads to cell death are primary causal pathways. There is now genetic evidence for each of these pathways, and a prevailing research strategy is to identify points in these pathways that could be exploited for therapeutic benefit. Today's basic science research continues to span a diverse array of fields, from genes and molecules, through cells and physiological systems, to the role of the environment and its interaction with genetic susceptibility. It is expected that these studies will continue to inform preventive strategies and better treatments for PD in the future. The Genetics and Cell Biology of Parkinson's disease One of the most remarkable transformations in PD research over the last decade was the identification of the first gene to be associated with PD, -synuclein. The discovery that genetic mutations could cause PD brought a sea change to a field that had previously focused only on environmental causes of the disease. Since the discovery of alpha synuclein in 1997, six genes have been linked to PD, including -synuclein, parkin, UCH-L1, DJ-1, PINK-1, and dardarin/LRRK2 - and evidence suggests the existence of additional, as yet unidentified genes. Gene discovery and gene characterization continue to be pivotal to clinical progress. Genetic mutations can provide a direct window into the cellular causes of disease, not only for individuals with hereditary disease, but for those with sporadic disease as well. Moreover, genetic mutations and single nucleotide polymorphisms (SNPs) - subtle variations in the genetic code that occurs across a population - can help clinicians identify who is at risk for the disease. Once neuroprotective and preventative therapies are developed, it will be crucial to target at risk patients early in disease for these therapies to have impact. Since the discovery of -synuclein, subsequent research has shown that synuclein plays a role in protein aggregation in dopaminergic neurons in both inherited and sporadic PD, generating translational research on aggregation inhibitors and synuclein knock-down strategies (such as small interfering RNAs, or siRNAs) as potential new treatments. Many studies suggest that protein accumulation is neurotoxin, in particular, studies showing triplication or duplication of synuclein genes, and thus synuclein protein, causes PD. However, other studies have demonstrated that the aggregation process may be a protective response to insult, and it still remains unclear as to which forms of synuclein during the aggregation process are toxic. Understanding the role of -synuclein may enable strategies to selectively block the harmful effects associated with this protein as a novel approach to treatment of PD. Other studies of proteins genetically implicated in PD continue to reveal potential therapeutic points of intervention - for example, mutant parkin may interfere with the disposal of misfolded proteins, leading to their subsequent aggregation, and may also adversely affect mitochondrial function; DJ-1 and PINK1 genes encode for proteins associated with mitochondria in neurons that may confer neuroprotection, thus when these genes are mutated, the loss of the normal function of these proteins leads to oxidative stress and development of the disease. Targeted manipulation of these proteins or their interacting partners will be important in modulating disease progression. More recently, scientists have begun characterization of the LRRK2 gene, which may account for a high percentage of familial and idiopathic PD. To date, 20 LRRK2 mutations have been linked to PD, accounting for approximately 7% of familial PD and for a significant fraction of sporadic PD cases. The most prevalent LRRK2 mutation is responsible for perhaps 40% of familial and sporadic PD in North African Arab populations, 30% of familial PD in Ashkenazi Jewish populations, up to 6% of familial cases in Europe, and up to 3% of apparently sporadic PD in Europe and North America. The clinical symptoms associated with LRRK2 mutations are frequently indistinguishable from idiopathic PD, suggesting that a therapeutic strategy directed against LRRK2 might be a key target in the treatment of PD. In addition, NINDS intramural and extramural researchers have also identified important genetic links between PD and Gaucher disease. Specifically, they now recognize that mutations in the glucocerebrosidase gene can contribute to the development of both disorders. This finding not only expands our understanding of the cellular biology of both diseases, but it also illustrates the surprising relationships that sometimes emerge between seemingly unrelated disorders. In addition to these successes, the NINDS Human Genetics Repository has banked over 10,000 samples, (5436 from PD and 5271 control subjects) with known causal genes including parkin, LRRK2, and synuclein triplication. Publicly available samples and data exist at http://locus.umdnj.edu/ninds for 1351 subjects with PD and approximately 100 with other forms of Parkinsonism. A whole genome study (SNP based analyses) is currently underway in the intramural program using these samples in PD to identify risk factors for sporadic disease. The NINDS has publicly posted clinical data and a whole genome SNP analysis from this study so far, for close to 300 control subjects, which has already been accessed by over 50 researchers to date. Table1. Clinical characteristics of Parkinson's disease cases Case Sex Age PMI Clinical histories 166 M 52 14.5 Severe, rapidly progressive PD; IDDM; CRF; depression 168 F 73 15.5 23 year hx of PD; depression; cortical plaques at autopsy did not meet criteria for AD 170 M 76 12.75 TURP 11 years before death; orthostatic hypotension; no evidence of MSA at post 171 M 83 5.5 4 year hx of PD; hypothyroidism; silent aspiration; no evidence of AD or MSA at post 172 M 84 10 12 year hx of PD (symptoms 6 years before dx); depression; no evidence of AD or MSA at post 174 F 82 13.5 Depression; discoid lupus erythematosus 175 M 79 16.5 10 year hx of PD; possible chronic lymphocytic leukemia; neurogenic bladder; no AD at post 182 M 77 15 37 year hx of PD; tonic-clonic seizures; visual hallucinations; focal spongiform vacuolizations 187 F 73 9.5 >20 year hx of PD 203 M 72 18 26 year hx of PD; s/p CABG_5; hx of smoking M, Male; F, female; CABG, coronary artery bypass grafting; CRF, chronic renal failure; hx, history; dx, diagnosis; IDDM, insulin-dependent diabetes mellitus; MSA, multisystem atrophy; PMI, postmortem interval (hours); post, postmortem examination; TURP, transurethral resection of the prostate; s/p, status post. 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